U.S. patent number 10,668,042 [Application Number 16/391,128] was granted by the patent office on 2020-06-02 for methods of reducing the risk of cardiovascular events in a subject.
This patent grant is currently assigned to Amarin Pharmaceuticals Ireland Limited. The grantee listed for this patent is Amarin Pharmaceuticals Ireland Limited. Invention is credited to Paresh Soni.
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United States Patent |
10,668,042 |
Soni |
June 2, 2020 |
Methods of reducing the risk of cardiovascular events in a
subject
Abstract
In various embodiments, the present disclosure provides methods
reducing the risk of cardiovascular events in a subject on statin
therapy by administering to the subject a pharmaceutical
composition comprising about 1 g to about 4 g of eicosapentaenoic
acid ethyl ester or a derivative thereof.
Inventors: |
Soni; Paresh (Mystic, CT) |
Applicant: |
Name |
City |
State |
Country |
Type |
Amarin Pharmaceuticals Ireland Limited |
Dublin |
N/A |
IE |
|
|
Assignee: |
Amarin Pharmaceuticals Ireland
Limited (Dublin, IE)
|
Family
ID: |
69884391 |
Appl.
No.: |
16/391,128 |
Filed: |
April 22, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
|
US 20200093777 A1 |
Mar 26, 2020 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62818514 |
Mar 14, 2019 |
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62813888 |
Mar 5, 2019 |
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62758387 |
Nov 9, 2018 |
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62735680 |
Sep 24, 2018 |
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62735670 |
Sep 24, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/366 (20130101); A61K 9/0053 (20130101); A61P
9/10 (20180101); A61K 31/232 (20130101); A61K
31/366 (20130101); A61K 2300/00 (20130101); A61K
31/232 (20130101); A61K 2300/00 (20130101); A61K
31/505 (20130101); A61K 31/40 (20130101) |
Current International
Class: |
A61K
31/232 (20060101); A61P 9/10 (20060101); A61K
9/00 (20060101); A61K 31/505 (20060101); A61K
31/40 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
2628305 |
|
May 2007 |
|
CA |
|
2653787 |
|
Dec 2007 |
|
CA |
|
2675836 |
|
Jul 2008 |
|
CA |
|
2724983 |
|
Nov 2009 |
|
CA |
|
2772378 |
|
Dec 2010 |
|
CA |
|
101252837 |
|
Aug 2008 |
|
CN |
|
273708 |
|
Jul 1988 |
|
EP |
|
277747 |
|
Aug 1988 |
|
EP |
|
0302482 |
|
Feb 1989 |
|
EP |
|
347509 |
|
Dec 1989 |
|
EP |
|
0460917 |
|
Dec 1991 |
|
EP |
|
606012 |
|
Jul 1994 |
|
EP |
|
0610506 |
|
Aug 1994 |
|
EP |
|
0641562 |
|
Mar 1995 |
|
EP |
|
0843972 |
|
May 1998 |
|
EP |
|
1125914 |
|
Aug 2001 |
|
EP |
|
1157692 |
|
Nov 2001 |
|
EP |
|
1296670 |
|
Apr 2003 |
|
EP |
|
1549299 |
|
Dec 2003 |
|
EP |
|
1743644 |
|
Jan 2007 |
|
EP |
|
1 790 339 |
|
May 2007 |
|
EP |
|
1 834 639 |
|
Sep 2007 |
|
EP |
|
1 982 710 |
|
Oct 2008 |
|
EP |
|
2022495 |
|
Feb 2009 |
|
EP |
|
2395991 |
|
Aug 2010 |
|
EP |
|
2308493 |
|
Apr 2011 |
|
EP |
|
2343066 |
|
Jul 2011 |
|
EP |
|
2719382 |
|
Apr 2014 |
|
EP |
|
2792746 |
|
Oct 2014 |
|
EP |
|
2635263 |
|
Feb 1990 |
|
FR |
|
2148713 |
|
Jun 1985 |
|
GB |
|
2221843 |
|
Feb 1990 |
|
GB |
|
2229363 |
|
Sep 1990 |
|
GB |
|
9901809.5 |
|
Jan 1999 |
|
GB |
|
2480146 |
|
Nov 2011 |
|
GB |
|
55227 |
|
Dec 1982 |
|
IL |
|
61035356 |
|
Feb 1986 |
|
JP |
|
04182426 |
|
Jun 1992 |
|
JP |
|
09-59206 |
|
Mar 1997 |
|
JP |
|
2001139981 |
|
May 2001 |
|
JP |
|
2003306690 |
|
Oct 2003 |
|
JP |
|
07 238598 |
|
Sep 2007 |
|
JP |
|
08 050367 |
|
Mar 2008 |
|
JP |
|
10-2006-0109988 |
|
Oct 2006 |
|
KR |
|
10-2007-0058460 |
|
Jun 2007 |
|
KR |
|
2290185 |
|
Dec 2006 |
|
RU |
|
2402326 |
|
Oct 2010 |
|
RU |
|
WO 1990/004391 |
|
May 1990 |
|
WO |
|
WO 1992/021335 |
|
Dec 1992 |
|
WO |
|
WO 1994/028891 |
|
Dec 1994 |
|
WO |
|
WO 1995/024459 |
|
Sep 1995 |
|
WO |
|
WO 1996/036329 |
|
Nov 1996 |
|
WO |
|
WO 1997/039759 |
|
Oct 1997 |
|
WO |
|
WO 1998/016216 |
|
Apr 1998 |
|
WO |
|
WO 1999/26583 |
|
Jun 1999 |
|
WO |
|
WO 1999/029316 |
|
Jun 1999 |
|
WO |
|
WO 2000/044361 |
|
Aug 2000 |
|
WO |
|
WO 2000/051573 |
|
Sep 2000 |
|
WO |
|
WO 2001/015552 |
|
Mar 2001 |
|
WO |
|
WO 2002/002105 |
|
Jan 2002 |
|
WO |
|
WO 2002/058793 |
|
Aug 2002 |
|
WO |
|
WO 2002/089787 |
|
Nov 2002 |
|
WO |
|
WO 2002/096408 |
|
Dec 2002 |
|
WO |
|
WO 2003/068216 |
|
Aug 2003 |
|
WO |
|
WO 2003/092673 |
|
Nov 2003 |
|
WO |
|
WO 2004/050913 |
|
Jun 2004 |
|
WO |
|
WO 2004/064716 |
|
Aug 2004 |
|
WO |
|
WO 2004/078166 |
|
Sep 2004 |
|
WO |
|
WO 2004/082402 |
|
Sep 2004 |
|
WO |
|
WO 2005/060954 |
|
Jul 2005 |
|
WO |
|
WO 2005/079797 |
|
Sep 2005 |
|
WO |
|
WO 2005/079853 |
|
Sep 2005 |
|
WO |
|
WO2005/102301 |
|
Nov 2005 |
|
WO |
|
WO 2005/123060 |
|
Dec 2005 |
|
WO |
|
WO 2005/123061 |
|
Dec 2005 |
|
WO |
|
WO 2006/017627 |
|
Feb 2006 |
|
WO |
|
WO 2006/029577 |
|
Mar 2006 |
|
WO |
|
WO 2006/062748 |
|
Jun 2006 |
|
WO |
|
WO 2006/096806 |
|
Sep 2006 |
|
WO |
|
WO 2007/011886 |
|
Jan 2007 |
|
WO |
|
WO 2007/016256 |
|
Feb 2007 |
|
WO |
|
WO 2007/017240 |
|
Feb 2007 |
|
WO |
|
WO 2007/073176 |
|
Jun 2007 |
|
WO |
|
WO 2007/075841 |
|
Jul 2007 |
|
WO |
|
WO 2007/091338 |
|
Aug 2007 |
|
WO |
|
WO 2007/128801 |
|
Nov 2007 |
|
WO |
|
WO 2007/142118 |
|
Dec 2007 |
|
WO |
|
WO 2008/004900 |
|
Jan 2008 |
|
WO |
|
WO 2008/045465 |
|
Apr 2008 |
|
WO |
|
WO 2008/088415 |
|
Jul 2008 |
|
WO |
|
WO 2008/106787 |
|
Sep 2008 |
|
WO |
|
WO 2008/115529 |
|
Sep 2008 |
|
WO |
|
WO 2008/145170 |
|
Dec 2008 |
|
WO |
|
WO 2009/004999 |
|
Jan 2009 |
|
WO |
|
WO2009/085386 |
|
Jul 2009 |
|
WO |
|
WO2009/085388 |
|
Jul 2009 |
|
WO |
|
WO 2010/028067 |
|
Mar 2010 |
|
WO |
|
WO 2010/093634 |
|
Aug 2010 |
|
WO |
|
WO 2010/127099 |
|
Nov 2010 |
|
WO |
|
WO 2010/127103 |
|
Nov 2010 |
|
WO |
|
WO2010/134614 |
|
Nov 2010 |
|
WO |
|
WO 2010/147994 |
|
Dec 2010 |
|
WO |
|
WO2011/028689 |
|
Mar 2011 |
|
WO |
|
WO 2011/038122 |
|
Mar 2011 |
|
WO |
|
WO2011/085211 |
|
Jul 2011 |
|
WO |
|
WO 2011/109724 |
|
Sep 2011 |
|
WO |
|
WO2012/074930 |
|
Jun 2012 |
|
WO |
|
WO 2012/074930 |
|
Jun 2012 |
|
WO |
|
WO2012/128587 |
|
Sep 2012 |
|
WO |
|
WO 2013/070735 |
|
May 2013 |
|
WO |
|
WO2013/103958 |
|
Jul 2013 |
|
WO |
|
WO2013/148136 |
|
Oct 2013 |
|
WO |
|
WO2014/004861 |
|
Jan 2014 |
|
WO |
|
WO2014/004993 |
|
Jan 2014 |
|
WO |
|
WO2014/005013 |
|
Jan 2014 |
|
WO |
|
WO 2014/057522 |
|
Apr 2014 |
|
WO |
|
WO2014/074552 |
|
May 2014 |
|
WO |
|
WO2014/130200 |
|
Aug 2014 |
|
WO |
|
WO2014/134466 |
|
Sep 2014 |
|
WO |
|
WO2014/143469 |
|
Sep 2014 |
|
WO |
|
WO2014/143523 |
|
Sep 2014 |
|
WO |
|
WO2015/021141 |
|
Feb 2015 |
|
WO |
|
WO2015/066512 |
|
May 2015 |
|
WO |
|
WO2015/195662 |
|
Dec 2015 |
|
WO |
|
WO2016/140949 |
|
Sep 2016 |
|
WO |
|
WO2018/213663 |
|
Nov 2018 |
|
WO |
|
Other References
A study of AMR101 to evaluate its ability to reduce cardiovascular
events in high risk patients with hypertriglyceridemia and on
statin (Reduce-It). Available at:
http://clinicaltrials.gov/show/NCT01492361. (3 pages). cited by
applicant .
Aarsetoey H, Gurndt H, Nygaard O. The Role of Long-Chained Marine
N-3 Polyunsaturated Fatty Acids in Cardiovascular Disease. Cardiol
Res Pract. 2012. Epub Dec. 13, 2012. cited by applicant .
Aarsland, et al., "On the Effect of Peroximsomal beta-Oxidation and
Carnitine Palmitoyltransferase Activity by Eicosapentaenoic Aid in
Live and Heart of Rats." Lipids, 25:546-548, (Sep. 1990). cited by
applicant .
Aas, V., et al., "Eicosapentaenoic acid (20:5 n-3) increases fatty
acid and glucose uptake in cultured human skeletal muscle cells."
Journal of Lipid Research, 47:366-374 (Feb. 2006). cited by
applicant .
Abbey, M., et al., "Effect of fish oil on lipoproteins,
lecithin:cholesterol acyltransferase, and lipidtransfer protein
activity in humans." Arterioscler. Thromb. Vasc. Biol. 10:85-94
(Jan./Feb. 1990). cited by applicant .
Abele GS, Aziz K. "Cholesterol crystals cause mechanical damage to
biological membranes: a proposed mechanism of plaque rupture and
erosion leading to arterial thrombosis." Clin. Cardiol. (Sep.
2005);28(9):413-420. cited by applicant .
Abelo A, Andersson TB, Antonsson M, et al. "Stereoselective
metabolism of omeprazole by human cytochrome P450 enzymes." Drug
Metab. Dispos. Aug. 28, 2000(8): 966-72. cited by applicant .
Ackman et al., "The `Basic` Fatty Acid Composition of Atlantic Fish
Oils: Potential Similarties Useful for Enrichment of
Polyunsaturated Fatty Acids by Urea Complexation," JAOCS, vol. 65,
1:136-138 (Jan. 1988). cited by applicant .
Adan, Y, et al., "Effects of docosahexaenoic and eicosapentaenoic
acid on lipid metabolism, eicosanoid production, platelet
aggregation and atherosclerosis." Biosci. Biotechnol. Biochem.
63(1), 111-119 (Jan. 1999). cited by applicant .
Adan, Y., et al., "Concentration of serum lipids and aortic lesion
size in female and male apo E-deficient mice fed docosahexaenoic
acid." Biosci. Biotechnol. Biochem. 63(2):309-313 (Feb. 1999).
cited by applicant .
Adorini et al., "Farnesoid X receptor targeting to treat
nonalcoholic steatohepatitis," Drug Discover Today,
14(17-18):988-997 (Sep. 2012)(available online May 28, 2012). cited
by applicant .
Agren JJ, Vaisanen S, Hanninen O, et al. "Hemostatic factors and
platelet aggregation after a fish-enriched diet or fish oil or
docosahexaenoic acid supplementation." Prostaglandins Leukot Essent
Fatty Acids (Oct. 1997) 57 (4-5): 419-21. cited by applicant .
Agren, J.J. et al., "Fatty acid composition of erythrocyte,
platelet, and serum lipids in strict vegans." Lipids 30:365-369
(Apr. 1995). cited by applicant .
Agren, J.J., et al., "Fish diet, fish oil and docosahexaenoic acid
rich oil lower fasting and postprandial plasma lipid levels." Eur J
Clin Nutr., 50:765-771. (Nov. 1996). cited by applicant .
Aguilar-Salinas et al., "High Prevalence of Low HDL Cholesterol
Concentrations and Mixed Hyperlipidemia in a Mexican Nationwide
Survey," J Lipid Res., (Aug. 2001), 42:1298-1307. cited by
applicant .
Ai M, Otokozawa S, Asztalos BF, Ito Y, Nakajima K, White CC,
Cupples LA, Wilson PW, Schaefer EJ. "Small dense LDL cholesterol
and coronary heart disease: results from the Framingham Offspring
Study." Clin. Chem. (Jun. 2010);56(6):967-976. cited by applicant
.
Ait-Said, et al., "Inhibition by eicosapentaenoic acid of
IL-1.beta.-induced PGHS-2 expression in human microvascular
endothelial cells: involvement of lipoxygenase-derived metabolites
and p38 MAPK pathway." Biohimicia et Biophysica Acta, 1631:66-85
(Feb. 2003). cited by applicant .
Albert CM, Campos H, Stampfer MJ, et al. Blood Levels of Long-Chain
n-3 Fatty Acids and the Risk of Sudden Death. N Engl J Med
346(15):1113-1138, 2002. cited by applicant .
Alberti K, et. al. Harmonizing the Metabolic Syndrome: A Joint
Interim Statement of the International Diabetes Federation Task
Force on Epidemiology and Prevention; National Heart, Lung, and
Blood Institute; American Heart Association; World Heart
Federation; International Atherosclerosis Society; and
International Association for the Study of Obesity. Circulation.
120:1640-1645; 2009. cited by applicant .
Alderman, J.D., et al., "Effect of a modified, well-tolerated
niacin regimen on serum total cholesterol, high density lipoprotein
cholesterol and the cholesterol to high density lipoprotein ratio,"
Am. J. Cardio, 64: 725-729.A (Oct. 1989). cited by applicant .
Alessandri, J-M., et al., "Estradiol favors the formation of
eicosapentaenoic acid (20:5n-3) and n-3 docosapentaenoic acid
(22:5n-3) from alpha-linolenic acid (18:3n-3) in SH-SY5Y
neuroblastoma cells." Lipids 43:19-28 (Jan. 2008). cited by
applicant .
Allard et al. "Nutritional assessment and hepatic fatty acid
composition in non-alcoholic fatty liver disease (NAFLD): a
cross-sectional study." J Hepatol. Feb. 2008;48(2):300-7. cited by
applicant .
Allred, C., et al., "PPAR.gamma.1 as a molecular target of
eicosapentaenoic acid in human colon cancer (HT-29) cells." J.
Nutr. 138:250-256 (Feb. 2008). cited by applicant .
Almeida et al., "Effect of nebicapone on the pharmacokinetics and
pharmacodynamics of warfarin in healthy subjects." Eur J Clin
Pharmacol. (Oct. 2008);64(10):961-6. cited by applicant .
Amarin Appoints Medpace as CRO for Two Phase 3 Cardiovascular
Trials, published Oct. 19, 2009 (2 pages). cited by applicant .
Amarin Corporation Announces First Patients Enrolled in Two Phase 3
Clinical Trials Assessing AMR101 for the Treatment of
Cardiovascular Disease [online], Amarin Corporation, Jan. 11, 2010
[retrieved Apr. 27, 2011], Retrieved from the Internet:
<http://inestor.amarincorp.com/releasedetail.cfm?ReleaseID=504380>
(2 pages). cited by applicant .
Amarin Corporation, Annual Report, Jun. 24, 2010 (245 pages
total)(submitted in three parts; Part I: Cover and pp. 1-39 (81
pages); Part II: pp. 40 through F-10 (81 pages); Part III: pp.
F11-F51 (83 pages)). cited by applicant .
Amarin Corporation, Executive Informational Overview, "Neurological
Disease-Focused Biopharmaceutical Opportunity," SEC filing dated
Oct. 11, 2005 (99 pages). cited by applicant .
Amarin Corporation, Globe Newsire press release, "Reduce-It.TM.
Cardiovascular Outcomes Study of Vascepa.RTM. (icosapent ethyl)
Capsules Met Primary Endpoint," Sep. 24, 2018 (4 pages). cited by
applicant .
Amarin Corporation, press release (Jan. 18, 2008)(1 page). cited by
applicant .
Amarin Presentation "Next Generation Lipid Modification in
Cardiovascular Disease," (Aug. 2011)(27 pages). cited by applicant
.
Amarin Presentation "Next Generation Lipid Modification in
Cardiovascular Disease," (Mar. 2010)(25 pages). cited by applicant
.
Amarin Proceeding to Phase 3 with AMR101 for Hypertriglyceridemia,
published Jul. 23, 2008 (1 page). cited by applicant .
Amarin, Next Generation Lipid Modification in Cardiovascular
Disease, Investor Meetings, Nov. 2010,
(http://files.shareholder.com/downloads/AMRN/Ox0x417754/AA72705F-1D67-4E1-
D-A989-5805E5CF0244/Investor_Presentation_2010_Nov_10.pdf, accessed
Jan. 6, 2015. cited by applicant .
Amarin's Vascepa.RTM. Briefing Document for the Endocrinologic and
Metabolic Drugs Advisory Committee Meeting dated Oct. 16, 2013,
(117 pages). cited by applicant .
American Heart Association. Heart Disease and Stroke
Statistics--2010 Update. Dallas, Texas: American Heart Association;
2010. cited by applicant .
Anand RG, Alkadri M, Lavie CJ, Milani RV. The Role of Fish Oil in
Arrhythmia Prevention. J Cardioplin Rehabil Preven. 2008;28:92-98.
cited by applicant .
Anber V, Griffin BA, McConnell M, Packard CJ, Shepherd J. Influence
of plasma lipid and LDL-subfraction profile on the interaction
between low density lipoprotein with human arterial wall
proteoglycans. Atherosclerosis. Aug. 1996;124(2):261-271. cited by
applicant .
Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines
for the management of patients with unstable
angina/non-ST-elevation myocardial infarction--executive summary. A
report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Writing Committee to
Revise the 2002 Guidelines for the Management of Patients With
Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed
in Collaboration with the American College of Emergency Physicians,
the Society for Cardiovascular Angiography and Interventions, and
the Society of Thoracic Surgeons Endorsed by the American
Association of Cardiovascular and Pulmonary Rehabilitation and the
Society for Academic Emergency Medicine. J Am Coll Cardiol
50:652-726, 2007. cited by applicant .
Anderson TJ, Gregoire J, Hegele RA, et al. 2012 update of the
Canadian Cardiovascular Society guidelines for the diagnosis and
treatment of dyslipidemia for the prevention of cardiovascular
disease in the adult. Can. J. Cardiol. Feb. 2013;29:151-167. cited
by applicant .
Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The
effect of cholesterol-lowering and antioxidant therapy on
endothelium-dependent coronary vasomotion. N. Engl. J. Med. Feb.
1995;332:488-493. cited by applicant .
Anderson, "Lipoprotein-Associated Phospholipase A2: An Independent
Predictor of Coronary Artery Disease Events in Primary and
Secondary Prevention," 101 Am. J. Cardiology 23F-33F (Jun. 2008).
cited by applicant .
Ando, M., et al., "Eicosapentanoic acid reduces plasma levels of
remnant lipoproteins and prevents in vivo peroxidation of LDL in
dialysis patients." J. Am. Soc. Nephrol., 10:2177-2184 (Oct. 1999).
cited by applicant .
Ando, Y., et al., "Positional distribution of highly unsaturated
fatty acids in triacyl-sn-glycerols of Artemia Nauplii enriched
with docosahexaenoic acid ethyl ester." Lipids 36:733-740 (Jul.
2001). cited by applicant .
Andrade, SE. et al., "Discontinuation of antihyperlipidaemic drugs_
do rates reported in clinical trials reflect rates in primary care
settings?" New Eng. J. Med. 332: 1125-1131. (Apr. 1995). cited by
applicant .
Andrews HE, Bruckdorfer KR, Dunn RC, Jacobs M. Low-density
lipoproteins inhibit endotheliumdependent relaxation in rabbit
aorta. Nature. May 1987;327:237-239. cited by applicant .
Angerer et al., "n-3 Polyunsaturated Fatty Acids and the
Cardiovascular System", Current Opinion in Lipidology, 11(1):57-63,
(Feb. 2000). cited by applicant .
Anil, Eliz, "The Impact of EPA and DHA on Blood Lipids and
Lipoprotein Metabolism: Influence of ApoE Genotype", Proceedings of
the Nutrition Society, 66:60-68, (Feb. 2007). cited by applicant
.
Annex to Rule 161 Response dated Apr. 16, 2012 (4 pages). cited by
applicant .
Antman E, Anbe D, Armstrong P, et al. ACC/AHA guidelines for the
management of patients with ST-elevation myocardial
infarction--executive summary. A report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to revise the 1999 guidelines for the
management of patients with acute myocardial infarction). J Am Coll
Cardiol 44:671-719, 2004. cited by applicant .
Aoki T et al. "Experience of the use of ethyl eicosapentaenoic acid
preparation (Epadel) in patients with arteriosclerosis obliterans
complicated with diabetes mellitus. A study of the long-term
effects on glycemic control and blood lipids," Rinsho to Kenkyu;
70:625-631. (1993) (with English translation). cited by applicant
.
Appendix A to Defendants' Invalidity Contentions,
3:14-CV-02550-MLC-DEA (D.N.J.), 478 pages (Dec. 5, 2014). cited by
applicant .
Appleton, Katherine M., et al., "Effects of n-3 long-chain
polyunsaturated fatty acids on depressed mood: systematic review of
published trials", Am. J. Clin. Nutr., 84(6):1308-1316, (Dec.
2006). cited by applicant .
Arca et al., "Treating statin-intolerant patients," Diabetes,
Metabolic Syndrome and Obesity: Targets and Therapy, 4:155-156
(Apr. 28, 2011). cited by applicant .
Armaganijan L, Lopes RD, Healey JS, Piccini JP, Nair GN, Morillo
CA. Do Omega-3 fatty acids prevent atrial fibrillation after open
heart surgery? A meta-analysis of randomized controlled trials.
Clinics. 2011;66(11):1923-1928. cited by applicant .
Arrol, S. et al., "The effects of fatty acids on apolipoprotein B
secretion by human hepatoma cells (HEP G2)," Atherosclerosis
150:255-264. (Jun. 2000). cited by applicant .
Arshad, A., et al., "Sudden cardiac death and the role of medical
therapy." Progress in Cardiovascular Diseases, vol. 50, No. 6,
420-438, (May/Jun. 2008). cited by applicant .
Arterburn, L., et al., "Distribution, interconversion, and dose
response of n-3 fatty acids in humans." Am J Clin Nutr.,
83:1467S-76S (Jun. 2006). cited by applicant .
Asahara, EPA Products What is the Clinical Significance of Epadel?
Obesity and Diabetes 10(6):903-905 (2011) (with English
translation). cited by applicant .
Asano, M., et al., "Eicosapentaenoic acid inhibits
vasopressin-activated Ca2q influx and cell proliferation in rat
aortic smooth muscle cell lines." European Journal of Pharmacology
379:199-209 (Aug. 1999). cited by applicant .
Asano, M., et al., "Inhibitory effects of .omega.-3 polyunsaturated
fatty acids on receptor-mediated non-selective cation currents in
rat A7r5 vascular smooth muscle cells." British Journal of
Pharmacology 120:1367-1375, (Apr. 1997). cited by applicant .
ASCEND Study Collaborative Group. Effects of n-3 fatty acid
supplements in diabetes mellitus. N Engl J Med, 379(16):1540-1550
(publication date Oct. 18, 2018; epublication date Aug. 26, 2018).
cited by applicant .
Ascenta Health "Fish Oil as Triglycerides vs. Ethyl Esters: Why
this Matters." (2015)(14 pages). cited by applicant .
Astarita et al., "Targeted lipidomics strategies for oxygenated
metabolites of polyunsaturated fatty acids," Biochim Biophys Acta,
1851(4):456-168 (Apr. 2015). cited by applicant .
Atorvastatin Package Leaflet, Reg. No. LSR-005205/08, Sep. 30, 2016
[retrieved Sep. 30, 2016] retrieved from the internet:
academ-clinic.ru/drugs/atorvastatin (6 pages). cited by applicant
.
ATP III guidelines, NIH publication No. 01-3305 (2001).(6 pages).
cited by applicant .
Attie AD, et al., "Relationship between stearoyl-CoA desaturase
activity and plasma trigylcerides in human and mouse
hypertriglyceridemia," J. Lipid Res. 2002;43:1899-907. cited by
applicant .
Ault, "Prescription omega-3 fatty acid formulation approved,"
Ob.Gyn.News, (Jan. 15, 2005). cited by applicant .
Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty
acid supplement use with cardiovascular disease risks:
Meta-analysis of 10 trials involving 77917 individuals. JAMA
Cardiol 3:225-34 (publication date Mar. 1, 2018; epublication date
Jan. 31, 2018). cited by applicant .
Avandia [package insert]. Research Triangle Park, NC:
GlaxoSmithKline; 2011.(45 pages). cited by applicant .
Avery et al., "Upper Gastrointestinal System," Integrating
Therapeutic and Complementary Nutrition, Edited by Mary Marian, CRC
Press (2006)(14 pages). cited by applicant .
Aviram M, Rosenblat M, Bisgaier CL, Newton RS. Atorvastatin and
gemfibrozil metabolites, but not the parent drugs, are potent
antioxidants against lipoprotein oxidation. Atherosclerosis. Jun.
1998; 138(2):271-280. cited by applicant .
Ayton, et al., "A pilot open case series of Ethyl-EPA
supplementation in the treatment of anorexia nervosa,"
Prostaglandins, Leukotrienes and Essential Fatty Acids 71, pp.
205-209. (Oct. 2004). cited by applicant .
Ayton, et al., "Rapid improvement of severe anorexia nervosa during
treatment with ethyl-eicosapentaenoate and micronutrients,"
European Psychiatry 19, pp. 317-319. (Aug. 2004). cited by
applicant .
Baigent, C., et al., "Efficacy and safety of cholesterol-lowering
treatment: prospective meta-analysis of data from 90,056
participants in 14 randomised trials of statins." Lancet;
366:1267-1278. (Oct. 2005). cited by applicant .
Baldwin RM, Ohlsson S, Pedersen RS, et al. Increased omeprazole
metabolism in carriers ofthe CYPZC19*17 allele; a pharmacokinetic
study in healthy volunteers.Br. J. Clin. Pharmacol. May 2008 65
(5): 767-74. cited by applicant .
Baldwin SJ, Clarke SE, Chenery RJ. Characterization of the
cytochrome P450 enzymes involved in the in vitro metabolism of
rosiglitazone. Br. J. Clin. Pharmacol. Sep. 1999;48:424-432. cited
by applicant .
Balk, E.M. et al., "Effects of omega-3 fatty acids on serum markers
of cardiovascular disease risk: a systematic review.
Atherosclerosis." 189:19-30. (Nov. 2006). cited by applicant .
Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of
eicosapentaenoic acid ethyl ester (AMR 101) therapy in
statin-treated patients with persistent high triglycerides (from
the ANCHOR study). Am J Cardiol Oct. 2012 110 (7): 984-92. cited by
applicant .
Ballantyne et al., "Abstract 15071: AMR101 Lowers Triglycerides,
Atherogenic Lipoprotein, Phospholipase A.sub.2, and
High-sensitivity C-reactive Protein Levels in Patients with High
Triglycerides and on Background Statin Therapy (the ANCHOR Study),"
Circulation, Lippincott Williams and Wilkins, vol. 124, No. 21,
Suppl., Nov. 22, 2011. cited by applicant .
Ballantyne et al., "Effects of icosapent ethyl on lipoprotein
particle concentration and the fatty acid desaturation index in
statiotreated patients with persistent high triglycerides (the
ANCHOR study)." Journ. Clin. Lipidology, 2013, 7(3):270-271. cited
by applicant .
Ballantyne et al., Influence of low-high density lipoprotein
cholesterol and elevated triglyceride on coronary heart disease
events and response to simvastatin therapy in 4S, Circulation,
104:3046-3051. (Dec. 2001). cited by applicant .
Bang HO, Dyerberg J. "Plasma lipids and Lipoproteins in Greenlandic
west coast Eskimos" Acta Med Scand, 192:85-94. (Jul./Aug. 1972).
cited by applicant .
Banga, A., et al., "Adiponectin translation is increased by the
PPAR.gamma. agonists pioglitazone and .omega.-3 fatty acids." Am J
Physiol Endocrinol Metab 296:480-489 (Mar. 2009). cited by
applicant .
Bangham et al., "Diffusion of univalent ions across the lamellae of
swolloen phospholipids." J. Mol. Biol. (Aug. 1965) 13(1):238-252.
cited by applicant .
Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM, "Fasting
Compared With Nonfasting Triglycerides and Risk of Cardiovascular
Events in Women," JAMA, 298:309-316 (Jul. 2007). cited by applicant
.
Barter et al., "Effectiveness of Combined Statin Plus Omega-3 Fatty
Acid Therapy for Mixed Dyslipidemia." Am. J. Cardiol.
102(8):1040-1045 (Oct. 15, 2008). cited by applicant .
Basu, A., et al., "Dietary Factors That Promote or Retard
Inflammation." Arterioscler. Thromb. Vasc. Biol. 26:995-1001 (May
2006). cited by applicant .
Baynes JW. Role of oxidative stress in development of complications
in diabetes. Diabetes. Apr. 1991;40(4):405-412. cited by applicant
.
Bays HE et al. "Prescription omega 3 fatty acids and their lipid
effects: physiologic mechanisms of action and clinical
implications," Expert Rev Cardiovasc Ther., 6:391-409. (Mar. 2008).
cited by applicant .
Bays HE, Ballantyne CM, Braeckman RA, Stirten WG, Soni PN.
Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid:
effects on circulating markers of inflammation from the MARINE and
ANCHOR studies. Am. J. Cardiovasc. Drugs. Feb. 2013;13(1):37-46.
cited by applicant .
Bays HE, Braeckman RA, Ballantyne CM, et al. Icosapent ethyl, a
pure EPA omega-3 fatty acid: Effects on lipoprotein particle
concentration and size in patients with very high triglyceride
levels (the MARINE study). J. Clin. Lipidol. Nov./Dec.
2012;6:565-572. cited by applicant .
Bays HE, Safety considerations with omega-3 fatty acid therapy. Am.
J. Cardiol. Mar. 2007 99 (6A): 35C-43C. cited by applicant .
Bays, H., Clinical Overview of Omacor: A Concentrated Formulation
of Omega-3 Polyunsaturated Fatty Acids, Am J Cardiol.;
98[suppl]:71i-76i (Aug. 2006). cited by applicant .
Bays, H., "Rationale for Prescription Omega-3-Acid Ethyl Ester
Therapy for Hypertriglyceridemia: A Primer for Clinicians," Drugs
of Today, 44(3); 205-246. (Mar. 2008). cited by applicant .
Bays, H.E., Eicosapenteenoic Acid Ethyl Ester (AMR101) Therapy in
Patients With Very High Triglyceride Levels (from the Multi-center,
plAcebo-controlled, Randomized, double-blINd, 12-week study with an
open-label Extension [MARINE] Trial) Am J Cardiol;108:682-690.
(Sep. 2011). cited by applicant .
Bays, H.E., et al., "Long-term up to 24-month efficacy and safety
of concomitant prescription omega-3-acid ethyl esters and
simvastatin in hypertriglyceridemic patients." Curr Med Res Opin.;
26:907-915. (Apr. 2010). cited by applicant .
Beal, M.F., Annals of Neurology, vol. 38, No. 3, "Aging, Energy,
and Oxidative Stress in Neurodegenerative Diseases", pp. 357-366,
(Sep. 1995). cited by applicant .
Beaumont et al., Design of Ester Prodrugs to Enhance Oral
Absorption of Poorly Permeable Compounds: Challenges to the
Discovery Scientist, Current Drug and Metabolism. (Dec. 2003)
4:461-485. cited by applicant .
Becker LB, Aufderheide TP, Geocadin RG, Callaway CW, Lazar RM,
Donnino MW, Nadkarni VM, Abella BS, Adrie C, Berg RA, Merchant RM,
O'Connor RE, Meltzer DO, Holm MB, Longstreth WT, Halperin HR. AHA
Consensus Statement: Primary Outcomes for Resuscitation Science
Studies: A Consensus Statement From the American Heart Association.
Circulation 2011; CIR. 0b013e3182340239 published online before
print Oct. 3 2011, doi:10.1161/CIR.0b013e3182340239. cited by
applicant .
Belarbi et al., "A process for high yield and scaleable recovery of
high purity eicosapentaenoic acid esters from microalgae and fish
oil," Enzyme and Microbail Technology 26:516-529 (Apr. 2000). cited
by applicant .
Belger et al., "Assessment of prefrontal activation by infrequent
visual targets and non-target noval stimuli in schisophrenia: a
function MRI study, " Presented at the 9th Biennial winter workshop
on schizophrenia, Davos, Switzerland, Feb. 7-13, 1998, Abstract in
Schizophrenia Research. vol. 29. No. 1/02, Jan. 1998. cited by
applicant .
Belikov, Pharmaceutical Chemistry in Two Parts, 1/General
Pharmaceutical Chemistry 43-47 (1993) (with English translation)(9
pages). cited by applicant .
Belmaker et al., "Addition of Omega-3 Fatty Acid to Maintenance
Medication Treatment for Recurrent Unipolar Depressive Disorder,"
Am. J. Psychiatry, 159:477-479 (Mar. 2002). cited by applicant
.
Belmaker, et al., "Omega-3 Eicosapentaenoic Acid in Bipolar
Depression: Report of a Small Open-Label Study," J Clin Psychiatry;
66:726-729. (Jun. 2005). cited by applicant .
Bender NK, Kraynak MA, Chiquette E, et al. Effects of marine fish
oils on the anticoagulation status of patients receiving chronic
warfarin therapy. J. Thromb. Thrombolysis Jul. 5, 1998 (3): 257-61.
cited by applicant .
Benistant, C., et al., "Docosapentaenoic acid (22:5, n-3):
metabolism and effect on prostacyclin production in endothelial
cells." Prostaglandins, Leukotrienes and Essential Fatty Acids,
55(4):287-292, (Oct. 1996). cited by applicant .
Benn et al., Improving Prediction of Ischemic Cardiovascular
Disease in the General Population Using Apolipoprotein B: The
Copenhagen City Heart Study, 27 Arteriosclerosis, Thrombosis, &
Ascular Biology 661 (Mar. 2007). cited by applicant .
Bennett et al., "Treatment of IgA nephropathy with eicosapentanoic
acid (EPA): a two-year prospective trial [Abstract Only]." Clin.
Nephrol. 31(3):128-131 (Mar. 1989). cited by applicant .
Berge, R.K., et al., "In contrast with docosahexaenoic acid,
eicosapentaenoic acid and hypolipidaemic derivatives decrease
hepatic synthesis and secretion of triacylglycerol by decreased
diacylglycerol acyltransferase activity and stimulation of fatty
acid oxidation." Biochem J.; 343(Pt 1):191-197. (Oct. 1999). cited
by applicant .
Berglund L, Burnzell JD, Goldberg AC, et al. Evaluation and
treatment of hypertriglyceridemia: an endocrine society clinical
practice guideline. J. Clin. Endocrinol. Metab. Sep. 2012 97 (9):
2969-89. cited by applicant .
Berliner JA, Watson AD. A role for oxidized phospholipids in
atherosclerosis. N. Engl. J. Med. Jul. 2005;353(1):9-11. cited by
applicant .
Bertelsen M, Anggard EE, Carrier MJ. Oxidative stress impairs
insulin internalization in endothelial cells in vitro.
Diabetologia. May 2001;44(5):605-613. cited by applicant .
Betteridge, D.J., "Diabetic dyslipidaemia: past, present and
future." Practical Diabetes Int, 21(2): 78-85. (Mar. 2004). cited
by applicant .
Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of
4-year cardiovascular event rates in stable outpatients at risk of
or with atherothrombosis. JAMA 304(12):1350-7 (publication date
Sep. 22, 2010; epublication date Aug. 30, 2010). cited by applicant
.
Bhatt DL, Fox KAA, Hacke W, et al; CHARISMA Investigators.
Clopidogrel and aspirin versus aspirin alone for the prevention of
atherothrombotic events. N Engl J Med. 354(16):1706-1717
(publication date Apr. 20, 2006; epublication date Mar. 12, 2006).
cited by applicant .
Bhatt DL, Hulot JS, Moliterno DJ, Harrington RA. Antiplatelet and
anticoagulation therapy for acute coronary syndromes. Circ Res
114(12):1929-43 (publication date Jun. 6, 2014). cited by applicant
.
Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of
Reduce-It: Reduction of Cardiovascular Events with Icosapent
Ethyl-Intervention Trial. Clin Cardiol 40:138-48 (publication date
Mar. 2017; epublication date Mar. 15, 2017). cited by applicant
.
Bhatt DL, Steg PG, Ohman EM, et al; REACH Registry Investigators.
International prevalence, recognition and treatment of
cardiovascular risk factors in outpatients with atherothrombosis.
JAMA. 295(2):180-189 (publication date Jan. 11, 2006). cited by
applicant .
Bhatt et al., "Cardiovascular Risk Reduction with Icosapent Ethyl
for Hypertiglyceridemia," N. Eng. J. Med., Nov. 10, 2018 (epub
ahead of print)(12 pages)(downloaded from nejm.org on Nov. 13, 2018
at https://www.nejm.org/doi/full/10.1056/NEJMoa1812792). cited by
applicant .
Bild et at., "Multi-Ethnic Study of Atherosclerosis: objectives and
design," Am J . Epidemiol 156(9):871-81 (Nov. 1, 2002). cited by
applicant .
Black et al., "Effect of intravenous eicosapentaenoic acid on
cerebral blood flow, edema, and brain prostaglandins in ischemic
gerbils", Prostaglandins, 28(4), pp. 545-546. (Oct. 1984). cited by
applicant .
Blankenhorn D.H. et al., "Beneficial effects of combined
colestipol-niacin therapy on coronary atherosclerosis and coronary
venous bypass grafts." JAMA 257: 3233-3240. (Jun. 1987). cited by
applicant .
Block, R. C., et al., "EPA and DHA in blood cell membranes from
acute coronary syndrome patients and controls." Atherosclerosis,
197(2):821-828 (Apr. 2008). cited by applicant .
Blumenthal, Advanced Studies in Medicine, 2:148-157 (2002). cited
by applicant .
Boden WE, Probstfield JL, Anderson T, Chaitman BR,
Desvignes-Nickens P, Koprowicz K, IJ McBride R, Teo K, Weintraub W.
and the Aim-High Investigators, "Niacin in patients with low hdl
cholesterol levels receiving intensive statin therapy," N. Engl. J.
Med. Dec. 2011;365:2255-2267. cited by applicant .
Bonaa, KH et al., Docosahexaenoic and Eicosapentaenoic acids in
plasma phospholipids are divergently associated with high density
lipoprotein in humans, Arterioscler. Thromb. Vasc. Biol.;12;675-681
(Jun. 1992). cited by applicant .
Bonnet et al., "Comparative Effects of 10-mg Versus 80-mg
Atorvastatin on High-Sensitivity C-Reactive Protein in Patients
with Stable Coronary Artery Disease: Results of the CAP
(Comparative Atorvastatin Pleiotropic Effects) Study," Clinical
Therapeutics. 30(12):2298-2313 (Dec. 2008). cited by applicant
.
Borchman D, Lamba OP, Salmassi S, Lou M, Yapped MC. The dual effect
of oxidation on lipid bilayer structure. Lipids. Apr.
1992;27(4):261-265. cited by applicant .
Bordin et al., "Effects of fish oil supplementation on
apolipoprotein B100 production and lipoprotein metabolism in
normolipidaemic males," Eur. J. Clin. Nutr. 52: 104-9 (Feb. 1998).
cited by applicant .
Borow et al., "Biologic plausibility, cellular effects, and
molecular mechanisms of eicosapentaenoic acid (EPA) in
atherosclerosis," Atherosclerosis, 242(1):357-66 (Sep. 2015). cited
by applicant .
Borthwick et al., "The effects of an omega-3 ethyl ester
concentrate on blood lipid concentrations in pateitns with
hyperlipidemia," Clin. Drug Investig. (1998) 15(5): 397-404. cited
by applicant .
Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S, Henry PD.
Impaired muscarinic endothelium-dependent relaxation and cyclic
guanosine 5'-monophosphate formation in atherosclerotic human
coronary artery and rabbit aorta. J. Clin. Invest. Jan.
1987;79:170-174. cited by applicant .
Bousserouel, S., et al., "Different effects of n-6 and n-3
polyunsaturated fatty acids on the activation of rat smooth muscle
cells by interleukin-1 beta." J. Lipid Res. 44:601-611 (Mar. 2003).
cited by applicant .
Bousserouel, S., et al., "Modulation of cyclin D1 and early growth
response factor-1 gene expression in interleukin-1beta-treated rat
smooth muscle cells by n-6 and n-3 olyunsaturated fatty acids."
Eur. J. Biochem. 271:4462-4473 Nov. 2004. cited by applicant .
Brady, L., et al., Increased n-6 polyunsaturated fatty acids do not
attenuate the effects of long-chain n-3 polyunsaturated fatty acids
on insulin sensitivity or triacylglycerol reduction in Indian
Asians. Am J Clin Nutr 79:983-91(Jun. 2004). cited by applicant
.
Braeckman et al., "Abstract 18549: Effects of AMR101, a Pure
Eicosapentaenoic Omega-3 Fatty Acid, on the Fatty Acid Profile in
Plasma and Red Blood Cells in Statin-Treated Patients with
Persistent High Triglycerides--Results from the ANCHOR study,"
Circulation 126(21S):A15071 (Nov. 20, 2012)(2 pages). cited by
applicant .
Braeckman et al., "Effect of Concomitant Icosapent Ethyl
(Eicosapentaenoic Acid Ethyl Ester) on Pharmacokinetics of
Atorvastatin," Clinical Drug Investigation. (Jan. 2015) (3)45-51.
cited by applicant .
Braeckman RA, Manku MS, Bays HE, Stirtan WG, Soni PN. Icosapent
ethyl, a pure EPA omega-3 fatty acid: effects on plasma and red
blood cell fatty acids in patients with very high triglyceride
levels (results from the MARINE study). Prostaglandins Leukot
Essent Fatty Acids. Sep. 2013;89(4):195-201. cited by applicant
.
Braeckman RA, Stirtan WG, Soni PN. Pharmacokinetics of
eicosapentaenoic acid in plasma and red blood cells after multiple
oral dosing with AMR101 (ethyleicosapentaenoic acid) in healthy
subjects [abstract]. Presented at: Congress of the International
Society for the Study of Fatty Acids and Lipids, Vancouver, Canada,
May 26-30, 2012. cited by applicant .
Braeckman RA, Stirtan WG, Soni PN. Pharmacokinetics of
eicosapentaenoic acid in plasma and red blood cells after multiple
oral dosing with icosapent ethyl in healthy subjects. Clin.
Pharmacol. Drug Dev. 2013;3:101-108. cited by applicant .
Braunersreuther V, Steffens S, Arnaud C, Pelli G, Burger F,
Proudfoot A, Mach F. A novel rantes antagonist prevents progression
of established atherosclerotic lesions in mice. Arterioscler.
Thromb. Vasc. Biol. Jun. 2008;28:1090-1096. cited by applicant
.
Breslow, J., "n-3 Fatty acids and cardiovascular disease." Am J
Clin Nutr., 83:1477S-82S (Jun. 2006). cited by applicant .
Brinton EA, Ballantyne CM, Bays HE, Kastelein JJ, Braeckman RA,
Soni PN. Effects of AMR101 on lipid and inflammatory parameters in
patients with diabetes mellitus-2 and residual elevated
triglycerides (200-500 mg/dl) on statin therapy at LDL-C goal: the
ANCHOR study.[abstract 629-P] Diabetes. 2012;61(suppl 1):A159-A160.
cited by applicant .
Brossard, N., et al., "Retroconversion and metabolism of
[13C]22:6n-3 in humans and rats after intake of a single dose of
[13C]22:6n-3-3-triacyylglycerols." Am. J. Clin. Nutr. 64:577-86
(Oct. 1996). cited by applicant .
Brouwer, I.A., et al., "Effect of fish oil on ventricular
tachyarrhythmia and death in patients with implantable cardioverter
defibrillators." JAMA. 295(22):2613-2619 (Jun. 2006). cited by
applicant .
Brovkovych V, Dobrucki LW, Brovkovych S, Dobrucki I, Do Nascimento
CA, Burewicz A, Malinski T. Nitric oxide release from normal and
dysfunctional endothelium. J. Physiol. Pharmacol. Dec.
1999;50:575-586. cited by applicant .
Brown et al., Simvastatin and Niacin, Antioxidant Vitamins, or the
Combination for the Prevention of Coronary Disease, N Engl J Med,
vol. 345, No. 22, 1583-1592 (Nov. 29, 2001). cited by applicant
.
Brown, A. J., et al., "Administration of n-3 Fatty Acids in the
Diets of Rats or Directly to Hepatocyte Cultures Results in
Different Effects on Hepatocellular ApoB Metabolism and Secretion."
Arterioscler. Thromb. Vasc. Biol. 19:106-114 (Jan. 1999). cited by
applicant .
Brown, A. J., et al., "Persistent changes in the fatty acid
composition of erythrocyte membranes after moderate intake of n-3
polyunsaturated fatty acids: study design and implications." Am.J.
Clin. Nutri. 54:668-73(Oct. 1991). cited by applicant .
Brown, G., et al., "Regression of coronary artery-disease as a
result of intensive lipid-lowering therapy in men with high levels
of apolipoprotein," B., N. Engl. J. Med. 323: 1289-1298. (Nov.
1990). cited by applicant .
Brownlee M. Biochemistry and molecular cell biology of diabetic
complications. Nature. Dec. 2001; 414(6865):813-820. cited by
applicant .
Bryhn, M., et al., "The bioavailability and pharmacodynamics of
different concentrations of omega-3 acid ethyl esters."
Prostaglandins, Leukotrienes and Essential Fatty Acids 75:19-24
(Jul. 2006). cited by applicant .
Budavari, S., Editor, "The Merck Index", Merck & Co., Inc., p.
725 item 4511 and p. 279 and item 2417 (1989). cited by applicant
.
Budoff, "Triglycerides and Triglyceride-Rich Lipoproteins in the
Causal Pathway of Cardiovascular Disease," Am. J. Cardiol.,
118(1):138-45 (Jul. 1, 2016). cited by applicant .
Bunting et al. "Depression in Parkinson's Disease". J Neurosci
Nurs.; 23(3):158-164. (Abstract Only) (Jun. 1991). cited by
applicant .
Burdge, G.C., et al., "Eicosapentaenoic and docosapentaenoic acids
are the principal products of a-linolenic acid metabolism in young
men." British Journal of Nutrition 88:355-363 (Oct. 2002). cited by
applicant .
Burdge, G.C., et al., "Lack of effect of meal fatty acid
composition on postprandial lipid, glucose and insulin responses in
men and women aged 50-65 years consuming their habitual diets."
British Journal of Nutrition, 96:489-500 (Sep. 2006). cited by
applicant .
Burdge, G.C., et al., "The effect of altering the 20:5n-3 and
22:6n-3 content of a meal on the postprandial incorporation of n-3
polyunsaturated fatty acids into plasma triacylglycerol and
non-esterified fatty acids in humans." Prostaglandins, Leukotrienes
and Essential Fatty Acids 77:59-65 (Jul. 2007). cited by applicant
.
Burr ML, Sweetham PM, Fehily AM. Diet and reinfarction. Eur Heart J
15:1152-1153, 1994. cited by applicant .
Burr, M. L., et al., "Effects of changes in fat, fish and fibre
intakes on death and myocardial reinfarction: Diet and reinfarction
trial." The Lancet, 2(8666):757-61 (Sep. 1989). cited by applicant
.
Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of
cardiovascular diseases in people with diabetes mellitus: a
scientific statement from the American Heart Association and the
American Diabetes Association. Diabetes Care. 2007;30: 162-172.
cited by applicant .
Calabresi, L., et al., "Omacor in familial combined hyperlipidemia:
effects on lipids and low density lipoprotein subclasses."
Atherosclerosis 148:387-396 (Feb. 2000). cited by applicant .
Calder PC. Omega-3 Fatty Acids and Inflammatory Processes.
Nutrients 2(3):355-374, 2010. cited by applicant .
Calder PC. The role of marine omega-3 (n-3) fatty acids in
inflammatory processes, atherosclerosis and plaque stability. Mol.
Nutr. Food Res. Jul. 2012;56(7):1073-1080. cited by applicant .
Campos, H., et al., "Lowdensity lipoprotein size, pravastatin
treatment, and coronary events." JAMA, 286:1468-1474 (Sep. 2001).
cited by applicant .
Canner P.L. et al., "Fifteen year mortality in Coronary Drug
Project patients: long-term benefit with niacin," J. Am. Coll.
Cardiol. 8. 1245-1255. (Dec. 1986). cited by applicant .
Cannon CP, Blazing MA, Giugliano RP, et al; Improve-It
Investigators. Ezetimibe added to statin therapy after acute
coronary syndromes. N Engl J Med. 372:2387-2397. cited by applicant
.
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate
lipid lowering with statins after acute coronary syndromes. N Engl
J Med 350(15):1495-1504 (publication date Apr. 8, 2004;
epublication date Mar. 8, 2004). cited by applicant .
Cao H, Wang X, Huang H, Ying SZ, Guy W, Wang T, Huang CX. Omega-3
Fatty Acids in the Prevention of Atrial Fibrillation Recurrences
after Cardioversion: A Meta-analysis of Randomized Controlled
Trials. Int Med. 2012;51:2503-2508. cited by applicant .
Cao, et al., "Cloning, Expression, and Chromosomal Locatlization .
. . ", Genomics, 49:327-331, (Apr. 15, 1998). cited by applicant
.
Cao, J., et al., "Incorporation and Clearance of Omega-3 Fatty
Acids in Erythrocyte Membranes and Plasma Phospholipids." Clinical
Chemistry 52(12):2265-2272 (Dec. 2006). cited by applicant .
Capuzzi, DM et al., "Efficacy and safety of an extended-release
niacin (Niaspan): a long-term study." Am. J. Cardiol. 82: 74U-81U.
(Dec. 17, 1998). cited by applicant .
Carlson, L.A. & Rosenhamer G., "Reduction of mortaility in the
Stockholm Ischaemic Heart Disease Secondary Prevention Study by
combined treatment with clofibrate and nicotinic acid." Acta Med.
Scand. 223, 405-418 (1988). cited by applicant .
Carlson, L.A., "Nicotinic acid: the broad spectrum lipid drug. A
50th Anniversary review", J. Int. Med., 258:94-114, (Aug. 2005).
cited by applicant .
Carrero et al., "Intake of Fish Oil, Oleic Acid, Folic Acid, and
Vitamins B-6 and E for 1 Year Decreases Plasma C-Reactive Protein
and Reduces Coronary Heart Disease Risk Factors in Male Patients in
a Cardiac Rehabilitation Program", pp. 384-390 (Feb. 2007). cited
by applicant .
Carrero, J.J. et al. "Efectos cardiovasculares de los acidos grasos
omega-3 y alternatives para incrementar su ingesta," Nutricion
Hospitalaria. (2005) (1) 63-69 [with English abstract]. cited by
applicant .
Carroll, D. N., et al., "Evidence for the Cardioprotective Effects
of Omega-3 Fatty Acids." Ann Pharmacother., 36:1950-6 (Dec. 2002).
cited by applicant .
Carulli et al., "Chenodeoxycholic acid and ursodeoxycholic acid
effects in endogenous hypertriglyceridemias. A controlled
double-blind trial." J. Clin. Pharmacol., 21(10):436-42 (Oct.
1981). cited by applicant .
Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ. The
effect on human tumor necrosis factor .alpha. and interleukin
1.beta. production of diets enriched in n-3 fatty acids from
vegetable oil or fish oil. Am J Clin Nutr. 1996;63:116-122. cited
by applicant .
Cavender MA, Steg PG, Smith SC, et al; REACH Registry
Investigators. Impact of diabetes mellitus on hospitalization for
heart failure, cardiovascular events, and death: outcomes at 4
years from the reduction of atherothrombosis for continued health
(REACH) registry. Circulation. 132(10):923-931 (publication date
Sep. 8, 2015; epublication date Jul. 7, 2015). cited by applicant
.
Cawood AL, Ding R, Napper FL, et al. Eicosapentaenoic acid (EPA)
from highly concentrated n-3 fatty acid ethyl esters is
incorporated into advanced atherosclerotic plaques and higher
plaque EPA is associated with decreased plaque inflammation and
increased stability. Atherosclerosis. 2010;212:252-259. cited by
applicant .
Cazzola, R., et al., "Age- and dose-dependent effects of an
eicosapentaenoic acid-rich oil on cardiovascular risk factors in
healthy male subjects." Atherosclerosis 193:159-167 Jul. 2007.
cited by applicant .
Ceci et al., "The effects of oral 5-hydroxytryptophan
administration on feeding behavior in obese adult female subjects,"
J Neural. Transm (1989) 76(2):109-117. cited by applicant .
Cefali, E.A., et al., "Aspirin reduces cutaneous flushing after
administration of an optimised extended-release niacin
formulation", Int. J. Clin. Pharmacol. & Ther., 45(2):78-88,
(Feb. 2007). cited by applicant .
Center for Drug Evaluation and Research. Application No. 21-853,
21654s016, (Omacor). Statistical Review and Evaluation: Clinical
Studies, Omacor (omega-3 acid ethyl ester) Capsules, 4 grams/day;
2007. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021853s000;%20-
021654s016_StatR.pdf. (Accessed Jan. 26, 2012) (156 pages). cited
by applicant .
Center for Drug Evaluation and Research. Approval Package for
Application No. 202057Orig1s000. Review--Vascepa (formerly AMR101),
373 pages (Jul. 26, 2012)(in two parts). cited by applicant .
Center for Drug Evaluation and Research. Approval Package for:
21-654 (Omacor/Lovaza). Statistical Review; 2004. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-654_Omacor_Admi-
nCorres_P1.pdf. Accessed Jan. 26, 2012. (54 pages). cited by
applicant .
Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism
underlying insulin resistance, diabetes, and cardiovascular
disease? The common soil hypothesis revisited. Arterioscler.
Thromb. Vasc. Biol. (May 2004);24(5):816-823. cited by applicant
.
Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small,
dense, low-density lipoproteins to oxidative modification in
subjects with the atherogenic lipoprotein phenotype, pattern B. Am.
J. Med. (Apr. 1993);94(4):350-356. cited by applicant .
Chan et al., "Effect of Atorvastatin and Fish Oil on Plasma
High-Sensitivity C-Reactive Protein Concentrations in Individuals
with Visceral Obesity", Clin. Chem., vol. 48, pp. 877-883 (2002).
cited by applicant .
Chan et al., Factorial Study of the Effects of Atorvastatin and
Fish Oil on Dyslipidaemia in Visceral Obesity, 32 Euro. J. Clinical
Investigation. 32(6):429-36 (Jun. 2002). cited by applicant .
Chan, D.C., et al., "Randomized controlled trial of the effect of
n-3 fatty acid supplementation on the metabolism of apolipoprotein
B-100 and chylomicron remnants in men with visceral obesity." Am J
Clin Nutr 77:300-7 (2003). cited by applicant .
Chang CL, Seo T, Du CB, Accili D, Deckelbaum RJ. n-3 Fatty Acids
Decrease Arterial Low-Density Lipoprotein Cholesterol Delivery and
Lipoprotein Lipase Levels in Insulin-Resistant Mice. Arterioscler
Thromb Vasc Biol. 2010;30(12):2510-2517. cited by applicant .
Chapman, M.J., et al., "Cholesteryl ester transfer protein: at the
heart of the action of lipid-modulating therapy with statins,
fibrates, niacin, and cholesteryl ester transfer protein
inhibitors." Eur Heart J., 31(2):149-164 (Jan. 2010). cited by
applicant .
Chatterjee SN, Agarwal S. Liposomes as membrane model for study of
lipid peroxidation. Free Radic. Biol. Med. 1988;4(1):51-72. cited
by applicant .
Chemical Book, Eicosapentaenoic acid ethyl ester, copyright 2010,
printed Jun. 16, 2011 from www.chemicalbook.com. (2010). cited by
applicant .
Chen, H., et al., "Eicosapentanoic acid inhibits
hypoxia-reoxygenation-induced injury by attenuating upregulation of
MMP-1 in adult rat myocytes." Cardiovascular Research 59:7-13 (Jul.
2003). cited by applicant .
Chen, H., et al., "EPA and DHA attenuate ox-LDL-induced expression
of adhesion molecules in human coronary artery endothelial cells
via protein kinase B pathway." Journal of Molecular and Cellular
Cardiology 35:769-775 (Jul. 2003). cited by applicant .
Chen, I.S., et al., "In vitro clearance of chylomicron
triglycerides containing (.omega.-3) eicosapentaenoate."
Atherosclerosis, 65:193-198 (1987). cited by applicant .
Cheng et al., "Antagonism of the prostaglandin D2 receptor 1
suppresses nicotinic acid-induces vasodilation in mice and humans,"
PNAS 103(17):6682-7 (Apr. 25, 2006). cited by applicant .
Childs, M.T., et al., "Divergent lipoprotein Responses to Fish Oils
With Various Ratios of Eicosapentaenoic Acid and Docasahexaenoic
Acid", American Society for Clinical Nutrition, 52:632-9, (Oct.
1990). cited by applicant .
Christensen, J. H., et al., "Effect of fish oil on heart rate
variability in survivors of myocardial infarction: a double blind
randomised controlled trial." BMJ, 312:677-678 (Mar. 16, 1996).
cited by applicant .
Christensen, M.S., et al., "Intestinal absorption and lymphatic
transport of eicosapentaenoic (EPA), docosahexaenoic (DHA), and
decanoic acids: dependence on intramolecular triacyiglycerol
structure." Am J Clin Nutr 61:56-61 (Jan. 1995). cited by applicant
.
Citizen Petition, Pronova BioPharma Norge AS, Docket No.
FDA-2009-P-0398-0001 (Aug. 4, 2009), at ii (Appendix), available at
www.regulations.gov. cited by applicant .
Classification of Hyperlipidaemias and Hyperlipoproteinaemias,
Bulletin of the World Health Organization, 43(6): 891-915 (1970).
cited by applicant .
Cleland, L.G., et al., "A Biomarker of n-3 compliance in patients
taking fish oil for rheumatoid arthritis." Lipids 38:419-424 (Apr.
2003). cited by applicant .
Clinical Trial NCT01047501, Effect of AMR101 (Ethyl Icosapentate)
on Triglyceride (Tg) Levels in Patients on Statins With High Tg
Levels (>200 and <500 mg/dL) (ANCHOR), ClinicalTrials.gov
[database online], U.S. National Institute of Health, Jan. 2010
[retrieved Apr. 27, 2011], Retrieved from the Internet:
<http://clinicaltrials.gov/ct2/show/NCT01047501> (3 pages).
cited by applicant .
Cohen AW, Combs TP, Scherer PE, Lisanti MP. Role of caveolin and
caveolae in insulin signaling and diabetes. American journal of
physiology. Endocrinology and metabolism. (Dec.
2003);285(6):E1151-1160. cited by applicant .
Cohen, J.D., et al., "30-year trends in serum lipids among United
States adults: results from the National Health and Nutrition
Examination Surveys II, III, and 1999-2006." Am J Cardiol.,
106:969-975. (Dec. 15, 2010). cited by applicant .
Cole et al., "Challenges and opportunities in the encapsulation of
liquid and semi-solid formulations into capsules for oral
administration," Advanced Drug Delivery Reviews, vol. 60, No. 6,
pp. 747-756. (Mar. 17, 2007). cited by applicant .
Colhoun, H. M., et al., "Primary prevention of cardiovascular
disease with atorvastatin in type 2 diabetes in the Collaborative
Atorvastatin Diabetes Study (CARDS): multicentre randomised
placebo-controlled trial." Lancet 364: 685-9 (Aug. 21-24, 2004).
cited by applicant .
Collins, N., et al., "Differences between Dietary Supplement and
Prescription Drug Omega-3 Fatty Acid Formulations: A Legislative
and Regulatory Perspective." Journal of the American College of
Nutrition, 27 (6):659-666 (Dec. 2008). cited by applicant .
Committee Roster for the Oct. 16, 2013 Meeting of the
Endocrinologic and Metabolic Drugs Advisory Committee, 2 pages.
(2013). cited by applicant .
Conklin, S. M., et al., "Serum .omega.-3 fatty acids are associated
with variation in mood, personality and behavior in
hypercholesterolemic community volunteers." Psychiatry Research
152: 1-10 (Jul. 30, 2007). cited by applicant .
Connor et al., "Seminars in thrombosis and hemostasis," 14:271-284.
(1988). cited by applicant .
Connor, W.E., "Importance of n-3 Fatty Acids in Health and
Disease", Am. J. Clin. Nutr., 71(1(S)):1715-1755, (Jan. 2000).
cited by applicant .
Conquer, J.A., et al., "Effect of supplementation with different
doses of DHA on the levels of circulating DHA as non-esterified
fatty acid in subjects of Asian Indian background. J Lipid Res."
39:286-292. (Feb. 1998). cited by applicant .
Conquer, J.A., et al., "Supplementation with an algae source of
docosahexaenoic acid increases (n-3) fatty acid status and alters
selected risk factors for heart disease in vegetarian subjects." J
Nutr., 126: 3032-3039. (Dec. 1996). cited by applicant .
Contacos et al. Effect of pravastatin and omega-3 fatty acids on
plasma lipids and lipoproteins in patients with combined
hyperlipidemia, pp. 1755-1762 (Dec. 1993). cited by applicant .
Coronary Artery Bypass Grafting, NIH, published online Feb. 23,
2012 (12 pages). cited by applicant .
Costanzo S, di Niro V, Castelnuovo AD, et al. Prevention of
postoperative atrial fibrillation in open heart surgery patients by
preoperative supplementation of n-3 polyunsaturated fatty acids: An
updated meta-analysis. Periop Manga.; Apr. 12, 2013 epub. cited by
applicant .
Coumadin [package insert], Princeton, NJ: Bristol-Myers Squibb;
2011. (10 pages). cited by applicant .
Cox PJ, Ryan DA, Hollis FJ, et al. Absorption, disposition, and
metabolism of rosiglitazone, a potent thiazolidinedione insulin
sensitizer, in humans. Drug Metab. Dispos. Jul. 2000;28:772-780.
cited by applicant .
Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP.
L-arginine improves endothelium-dependent vasodilation in
hypercholesterolemic humans. J. Clin. Invest. Oct.
1992;90:1248-1253. cited by applicant .
Crevel et al., "Allergenicity of Refined Vegetable Oils," Food and
Chemical Toxicology, 38, pp. 385-393 (Apr. 2000). cited by
applicant .
Criqui, M., "Triglycerides and Coronary Heart Disease Revisited
(Again)," vol. 147 No. 6, pp. 425-427 (Sep. 18, 2007). cited by
applicant .
Cromwell et al., "LDL particle number and risk of future
cardiovascular disease in the Framingham Offspring
Study--Implications for LDL Management," Journal of Lipidololgy.
(Dec. 2007) 1, 583-592. cited by applicant .
Crowe, F. L., et al., "Serum phospholipid n-3 long-chain
polyunsaturated fatty acids and physical and mental health in a
population-based survey of New Zealand adolescents and adults." Am
J Clin Nutr 86:1278-85 (Nov. 2007). cited by applicant .
Cruz et al., "The metabolic syndrome in children and adolescents,"
Curr. Diab. Rep., vol. 4(1):53-62 (Feb. 2004). cited by applicant
.
Culhane et al., "Rosuvastatin for the treatment of
hypercholesterolemia," Pharmacotherapy, 25(7):990-1000 (Jul. 2005).
cited by applicant .
Daggy, B., et al., Dietary fish oil decreases VLDL production
rates. Biochimica et Biophysics Acta 920: 293-300 (Aug. 15, 1987).
cited by applicant .
Dall et al., "Clinical utility of low-density lipoprotein particle
measurement in management of cardiovascular disease: a case
report," Research Reports in Clin. Cardiol., vol. 2, pp. 57-62
(2011). cited by applicant .
Das, U.N., Essential fatty acids as possible mediators of the
actions of statins. Prostaglandins, Leukotrienes and Essential
FattyAcids 65(1):37-40, (Jul. 2001). cited by applicant .
Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of
inflammatory markers and advanced lipoprotein testing: advice from
an expert panel of lipid specialists. J. Clin. Lipidol. Sep./Oct.
2011;5:338-367. cited by applicant .
Davidson MH, et al., Effects of prescription omega-3-acid ethyl
esters on lipo protein particle concentrations, apolipoproteins Al
and CIII, and lipoprotein-associated phospholipase A.sub.2 mass in
statin-treated subjects with hypertrigylceridemia, J.Clin. Lipid.,
vol. 3(5), pp. 332-340 (Oct. 2009). cited by applicant .
Davidson MH, Rosenson RS, Maki KC, Nicholls SJ, Ballantyne CM,
Mazzone T, Carlson DM, Williams LA, Kelly MT, Camp HS, Lele A,
Stolzenbach JC. Effects of fenofibric acid on carotid intima-media
thickness in patients with mixed dyslipidemia on atorvastatin
therapy: Randomized, placebo-controlled study (first).
Arterioscler. Thromb. Vasc. Biol. Jun. 2014;34:1298-1306. cited by
applicant .
Davidson MH, Stein EA, Bays HE et al. "Efficacy and tolerability of
adding prescription omega-3 fatty acids 4 g/d to simvastatin 40
mg/d in hypertriglyceridemic patients: an 8-week, randomized,
double-blind, placebo-controlled study," Clin Ther., 29:1354-1367.
(2007). cited by applicant .
Davidson MH., "Mechanisms for the hypotriglyceridemic effect of
marine omega 3 fatty acids." Am J Cardiol 98(4A):27i-33i. (2006).
cited by applicant .
Davidson, M.H., et al., "Effects of docosahexaenoic acid on serum
lipoproteins in patients with combined hyperlipidemia: a
randomized, doubleblind, placebo-controlled trial." J Am Coll
Nutr., 16:236-243. (1997). cited by applicant .
Davies et al., "Rapid separation of LDL subclasses by iodixanol
gradient ultracentrifugation," Clin. Chem., 49(11):1865-72. (Nov.
2003). cited by applicant .
Davies-Tuck et al., "Total cholesterol and triglycerides are
associated with development of new bone marrow lesions in
asymptomatic middle-aged women--a prospective cohort study,"
Arthritis Research & Therapy. (2009) pp. 1-7. cited by
applicant .
De Caterina, R, et al., "Control of Endothelial Leukocyte Adhesion
Molecules by Fatty Acids." Lipids, vol. 31:S57-S63 (1996). cited by
applicant .
De Caterina, R., et al., "The Omega-3 fatty acid docosahexaenoate
reduces cytokine-induced expression of proatherogenic and
proinflammatory proteins in human endothelial cells." Arterioscler.
Thromb. Vasc. Biol. 14:1829-1836 (1994). cited by applicant .
De Graaf J, Hak-Lemmers HL, Hectors MP, Demacker PN, Hendriks JC,
Stalenhoef AF. Enhanced V susceptibility to in vitro oxidation of
the dense low density lipoprotein subfraction in healthy subjects.
Arterioscler. Thromb. 1991;11(2):298-306. cited by applicant .
De Morais et al., "Evaluation of lipid extraction and fatty acid
composition of human plasma," Rev. Bras. Hematol. Hemoter.
32(6):439-443 (2010). cited by applicant .
Deckelbaum R. J., et al., "Conclusions and recommendations from the
symposium, Beyond Cholesterol: Prevention and Treatment of Coronary
Heart Disease with n-3 Fatty Acids." Am J Clin Nutr 87:2010S-12S
(2008). cited by applicant .
Defendants' Invalidity Contentions, 3:14-CV-02550-MLC-DEA (D.N.J.),
520 pages (Dec. 5, 2014). cited by applicant .
Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB
(D.N.J.), 901 pages (Dec. 5, 2014). cited by applicant .
DeMets DL, Lan KK. Interim Analysis: the Alpha Spending Function
Approach. Stat Med 1994;13(13-14):1341-52. cited by applicant .
Dewailly, E. et al., "n-3 Fatty acids and cardiovascular disease
risk factors among the Inuit of Nunavik." Am J Clin Nutr 74:464-73
(2001). cited by applicant .
Dewey FE, Gusarova V, O'Dushlaine C, et al. Supplement to:
Inactivating variants in ANGPTL4 and risk of coronary artery
disease. N Engl J Med. DOI: 10.1056/NEJMoa1510926; 2016. cited by
applicant .
Di Spirito, M., Morelli, G., Doyle, R.T., Johnson, J. &
McKenney, J. Effect of omega-3-acid ethyl esters on steady-state
plasma pharmacokinetics of atorvastatin in healthy adults. Expert
Opin. Pharmacother. 9, 2939-2945 (2008). cited by applicant .
Diagnostic and Statistical Manual of Mental Disorders, 4.Ed. Text
revision, published by the American Psychiatric Assoc., pp. 154-163
and 369-381 (2000). cited by applicant .
Diagnostic and Statistical Manual of Mental Disorders, 4.sup.th
Ed., published by the American Psychiatric Assoc., pp. 285-286,
(1994). cited by applicant .
Dijan, P., et al., Proc. Natl. Acad. Sci., vol. 93, "Codon repeats
in genes associated with human diseases: Fewer repeats in the genes
of nonhuman primates and nucleotide substitutions concentrated at
the sites of reiteration," pp. 417-421, (1996). cited by applicant
.
Dijk, J. M., et al., "Carotid intima-media thickness and the risk
of new vascular events in patients with manifest atherosclerotic
disease: the SMART study." European Heart Journal 27:1971-1978
(2006). cited by applicant .
Din et al., "Omega 3 fatty acids and cardiovascular
disease--fishing for a natural treatment," BMJ, vol. 327, No. 7430,
pp. 30-35 (2004). cited by applicant .
Djousse L, Akinkuolie AO, Wu JHY, Ding EL, Gaziano JM. Fish
consumption, omega-3 fatty acids and risk of heart failure: A
meta-analysis. Clin Nutr. 2012;31:846-853. cited by applicant .
Do R, Stitziel NO, Won HH, et. al. Exome sequencing identifies rare
LDLR and APOA5 alleles conferring risk for myocardial infarction.
Nature. 2015;518(7537):102-106. cited by applicant .
Do R, Willer CJ, Schmidt EM, et al. Common variants associated with
plasma triglycerides and risk for coronary artery disease. Nat
Genet 2013:45(11):1345-52. cited by applicant .
Dodin, S., et al., "Flaxseed on cardiovascular disease markers in
healthy menopausal women: a randomized, double-blind,
placebo-controlled trial." Nutrition 24:23-30 (2008). cited by
applicant .
Doi M, Nosaka K, Miyoshi T, et al. Early eicosapentaenoic acid
treatment after percutaneous coronary intervention reduced acute
inflammatory responses and ventricular arrhythmias in patients with
acute myocardial infarction: A randomized controlled study. Int J
Cardiol., 176(3):577-82 (publication date Oct. 20, 2014;
epublication date Aug. 19, 2014). cited by applicant .
Dolecek, "Epidemiological Evidence of Relationships Between Dietary
Polyunsaturated Farry Acids and Morality in the Multiple Risk
Factor Intervention Trial", Society of Experimental Biology and
Medicine, 200(2):177-182, (1991). cited by applicant .
Draft Agenda for the Oct. 16, 2013 Meeting of the Endocrinologic
and Metabolic Drugs Advisory Committee, 2 pages. cited by applicant
.
Draft Meeting Roster for the Oct. 16, 2013 Meeting of the
Endocrinologic and Metabolic Drugs Advisory Committee, 2 pages.
cited by applicant .
Draft Questions for the Oct. 16, 2013 Meeting of the Endocrinologic
and Metabolic Drugs Advisory Committee, 1 page. cited by applicant
.
Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial
dysfunction in coronary microcirculation of hypercholesterolaemic
patients by l-arginine. Lancet. 1991;338:1546-1550. cited by
applicant .
Dullenmeijer, C., et al., "n-3 Fatty acid proportions in plasma and
cognitive performance in older adults." Am J Clin Nutr 86:1479-85
(2007). cited by applicant .
Duncan, R. E., et al., "Regulation of HMG-CoA reductase in MCF-7
cells by genistein, EPA, and DHA, alone and in combination with
mevastatin." Cancer Letters 224:221-228 (2005). cited by applicant
.
Durrington PN et al. "An omega 3 poly unsaturated fatty acid
concentrate administered for one year decreased triglycerides in
simvastatin treated patients with coronary heart disease and
persistent Hypertriglyceridemia," Heart, 85:544-48 (2001). cited by
applicant .
Dwyer, J. H., et al., "Arachidonate 5-Lipoxygenase Promoter
Genotype, Dietary Arachidonic Acid, and Atherosclerosis." N. Engl.
J. Med., 350:1 (2004). cited by applicant .
Dyerberg, J., et al., "Marine Oils and Thrombogenesis." Prog. Lipid
Res. 21:255-269 (1982). cited by applicant .
Egert, S., et al., "Dietary alpha-linolenic acid, EPA, and DHA have
differential effects on LDL fatty acid composition but similar
effects on serum lipid profiles in normolipidemic humans." J Nutr.,
139:861-868 (2009). cited by applicant .
Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M, Komatsu R,
Matsuo T, Itabe H, Takano T, Tsukamoto Y, Yoshiyama M, Takeuchi K,
Yoshikawa J, Becker AE. Elevated levels of oxidized low density
lipoprotein show a positive relationship with the severity of acute
coronary syndromes. Circulation. 2001;103(15):1955-1960. cited by
applicant .
Eilat-Adar et al. "Association of Intentional Changes in Body
Weight with Coronary Heart Disease Event Rates in Overweight
Subjects who have an Additional Coronary Risk Factor," Amer. Journ.
Epidemiol.161(4)pp. 352-358 (Sep. 9, 2004). cited by applicant
.
Eisenberg S, Bilheimer DW, Levy RI, Lindgren FT. "On the metabolic
conversion of human plasma very low density lipoprotein to low
density lipoprotein," Biochim Biophys Acta, 326:361-77 (1973).
cited by applicant .
Eisenberg S, Rachmilewitz D. "Metabolism of rat plasma very low
density lipoprotein. I. Fate in circulation of the whole
lipoprotein," Biochim Biophys Acta, 326:378-90 (1973). cited by
applicant .
El-Serag HB, Graham DY, Satia JA, et al. Obesity is an independent
risk factor for GERD symptoms and erosive esophagitis. Am. J.
Gastroenterol. Jun. 2005 100 (6):1243-50. cited by applicant .
Elam, M.B., et al., "Effect of niacin on lipid and lipoprotein
levels and glycemic control in patients with diabetes and
peripheral arterial disease study: a randomized trial", The ADMIT
[Arterial Disease Multiple Intervention Trial] JAMA, 284:1263-1270,
(2000). cited by applicant .
El-Saadani M, Esterbauer H, El-Sayed M, Gober M, Nassar AY, Jurgens
G. A spectrophotometric assay for lipid peroxides in serum
lipoproteins using commercially available reagent. J. Lipid Res.
1989;30:627-630. cited by applicant .
El-Sohemy, A., et. al., "Regulation of Mevalonate Synthesis in Low
Density Lipoprotein Receptor Knockout Mice Fed n-3 or n-6
Polyunsaturated Fatty Acids." Lipids, 34 (10):1037-43 (1999). cited
by applicant .
Emsley et al., "Randomized, Placebo-Controlled Study of
Ethyl-Eicosapentaenoic Acid as Supplemental Treatment in
Schizophrenia," Am. J. Psychiatry, 159:1596-1598 (2002). cited by
applicant .
Endo et al., "The Effects of Dietary Fatty Acids on Serum Lipids
and Plasma Prostaglandin Levels in the Treatment of Obesity,"
Japanese Journal of Pediatric Gastroenterology and Nutrition
7(1):67-72 (Apr. 15, 1993) (with English translation)(22 pages).
cited by applicant .
ENews, "Cholesterol Crystals Induce Atherosclerosis-Associated
Inflammation in Mice," 1-4 (Jun. 14, 2010)(4 pages). cited by
applicant .
Engler, et al., "Docosahexaenoic acid restores endothelial function
in children with hyperlipidemia: results from the EARLY Study."
International Journal of Clinical Pharmacology and Therapeutics,
vol. 42--No. Dec. 2004 (672-679). (2004). cited by applicant .
Engler, M.B., et al., "Mechanisms of vasorelaxation induced by
eicosapentaenoic acid (20:5n-3) in WKY rat aorta." British Journal
of Pharmacology 131:1793-1799 (2000). cited by applicant .
Engler, M.M., et al., "The effects of a diet rich in
docosahexaenoic acid on organ and vascular fatty acid composition
in spontaneously hypertensive rats." Prostaglandins, Leukotrienes
and Essential Fatty Acids 61(5):289-295 (1999). cited by applicant
.
Ennis JL, Cromwell WC. Clinical utility of low-density lipoprotein
particles and apolipoprotein Bin patients with cardiovascular risk.
J. Fam. Pract. 2013;62:1-8. cited by applicant .
Epadel--PubChem CID 9831415, Retrieved on Apr. 9, 2014 [Retrieved
from the internet]
<URL:http://pubchem.ncbi.nlm.nih.gov/compound/9831415> (19
pages). cited by applicant .
Epadel 1990 and JELIS Study (4 pages). cited by applicant .
Epadel Capsules 300, Japan Pharmaceutical Reference 369-371 (2nd
ed.) (1991). (5 pages). cited by applicant .
Epadel drug information brochure (2000), certified English
translation(36 pages). cited by applicant .
Epadel Package Insert 2007 (with Translation)(6 pages). cited by
applicant .
Epadel Summary of Product Characteristics (SPC), Mochida
Pharmaceutical Co., Ltd. Tokyo, Japan, Oct. 2013. cited by
applicant .
Epadel.RTM. [Complete prescribing information]. Update (Version 5).
Tokyo, Japan: Mochida Pharmaceutical; Jan. 2007 (9 pages). cited by
applicant .
Epanova.RTM. (omega-3-carboxylic acids) capsules, for oral use,
Prescribing information, 5 pgs., AstraZeneca Pharmaceuticals LP,
(Revised: Mar. 2017)(5 pages). cited by applicant .
Eritsland J, Arnesen H, Gronseth K, et al. Effect of dietary
supplementation with n-3 fatty acids on coronary artery bypass
graft patency. Am. J. Cardiol. Jan. 1996 77 (1):31-6. cited by
applicant .
Eritsland J, Arnesen H, Seljeflot I, et al. Long-term effects of
n-3 polyunsaturated fatty acids on haemostatic variables and
bleeding episodes in patients with coronary artery disease. Blood
Coagul. Fibrinolysis Feb. 6, 1995 (1): 17-22. cited by applicant
.
Errata to the FDA Briefing Document Endocrinologic and Metabolic
Drug Advisory Committee Meeting Oct. 16, 2013, 1 page. cited by
applicant .
Esposito, "Effect of a Mediterranean-Style Diet on Endothelial
Dysfunction and Markers ofVascular Inflammation in the Metabolic
Syndrome: A Randomized Trial", Journal of the American Medical
Association, 2004, 292(12), 1440-1446. cited by applicant .
Essentialis Inc. press release, "Essentialis Meets Primary Endpoint
in Phase 2b Trial of DCCR for Treatement of Hypertriglyceridemia
and is Granted Extensive Patent Coverage in the US," PR Newswire
(May 17, 2009)( 2 pages). cited by applicant .
Exhibit A to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 48 pages (Dec. 5, 2014). cited by
applicant .
Exhibit B to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 6 pages (Dec. 5, 2014). cited by
applicant .
Exhibit C to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 14 pages (Dec. 5, 2014). cited by
applicant .
Exhibit D to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 19 pages (Dec. 5, 2014). cited by
applicant .
Exhibit E to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 6 pages (Dec. 5, 2014). cited by
applicant .
Exhibit F to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 10 pages (Dec. 5, 2014). cited by
applicant .
Exhibit G to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 21 pages (Dec. 5, 2014). cited by
applicant .
Exhibit H to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 10 pages (Dec. 5, 2014). cited by
applicant .
Exhibit I to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 14 pages (Dec. 5, 2014). cited by
applicant .
Exhibit J to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 13 pages (Dec. 5, 2014). cited by
applicant .
Exhibit K to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 5 pages (Dec. 5, 2014). cited by
applicant .
Exhibit L to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 5 pages (Dec. 5, 2014). cited by
applicant .
Exhibit M to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 7 pages (Dec. 5, 2014). cited by
applicant .
Exhibit N To Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 15 pages (Dec. 5, 2014). cited by
applicant .
Exhibit O to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 6 pages (Dec. 5, 2014). cited by
applicant .
Exhibit P to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 17 pages (Dec. 5, 2014). cited by
applicant .
Exhibit Q to Defendants' Joint Invalidity Contentions,
3:14-CV-02550-MLC-TJB (D.N.J.), 64 pages (Dec. 5, 2014). cited by
applicant .
Faggin, E., et al., "Fish Oil Supplementation Prevents Neointima
Formation in Nonhypercholesterolemic Balloon-Injured Rabbit Carotid
Artery by Reducing Medial and Adventitial Cell Activation."
Arterioscler. Thromb. Vasc. Biol., 20:152-163 (2000). cited by
applicant .
FDA Briefing Document, Endocrinologic and Metaboloic Drugs Advisory
Committee Meeting, dated Oct. 16, 2013, available publicly at least
as of Oct. 16, 2013, 115 pages. cited by applicant .
FDA News Release, "FDA approves new orphan drug Kynamro to treat
inherited cholesterol disorder," U.S. Food and Drug Administration,
Protecting and Promoting Your Health (Jan. 29, 2013)(2 pages).
cited by applicant .
Fer, M., et al., "Metabolism of eicosapentaenoic and
docosahexaenoic acids by recombinant human cytochromes P450."
Archives of Biochemistry and Biophysics 471:116-125 (2008). cited
by applicant .
Ferns, G., et al., "Investigation and management of
hypertriglyceridaemia." J. Clin. Pathol. 61:1174-1183 (2008). cited
by applicant .
Feron O, Dessy C, Desager JP, Balligand JL.
Hydroxy-methylgluataryl-coenzyme a reductase inhibition promotes
endothelial nitric oxide synthase activation through a decrease in
caveolin abundance. Circulation. 2001;103:113-118. cited by
applicant .
Final Agenda for the Oct. 16, 2013 Meeting of the Endocrinologic
and Metabolic Drugs Advisory Committee, 2 pages. cited by applicant
.
Final Meeting Roster for the Oct. 16, 2013 Meeting of the
Endocrinologic and Metabolic Drugs Advisory Committee, 2 pages.
cited by applicant .
Final Questions for the Oct. 16, 2013 Meeting of the Endocrinologic
and Metabolic Drugs Advisory Committee, 1 page. cited by applicant
.
Finnen et al., "Purification and characterisation of phospholipase
A2 from human epidermis, ", Biochemical Society Trans,19(2):91S,
1991. cited by applicant .
Fischer, R., et al., "Dietary n-3 polyunsaturated fatty acids and
direct renin inhibition improve electrical remodeling in a model of
high human renin hypertension." Hypertension 51:540-546 (2008).
cited by applicant .
Fisher et al., Journal of Biological Chemistry (2001) 276(3)
27855-27863. cited by applicant .
Flaten, H., et al., "Fish-oil concentrate: effects on variables
related to cardiovascular disease." Am. J. Clin. Nutr. 52:300-306
(1990). cited by applicant .
Food and Drug Administration (FDA), (2005) NIASPAN niacin extended
release tablets. cited by applicant .
Food and Drug Administration (FDA), (2005) Tablets ZOCOR.RTM.
(SIMVASTATIN). cited by applicant .
Ford, E. S, et al., "Hypertriglyceridemia and Its Pharmacologic
Treatment Among US Adults." Arch, Intern. Med., 169(6): 572-78
(2009). cited by applicant .
Fraker TD, Fihn SD. Writing on behalf of the 2002 Chronic Stable
Angina Writing Committee. 2007 chronic angina focused update of the
ACC/AHA guidelines for the management of patients with chronic
stable angina. A Report of the ACC/AHA Task Force on Practice
Guidelines. Circulation 50:2264-2274, 2007. cited by applicant
.
Frangou et al., "Efficacy of ethyl-eicosapentaenoic acid in bipolar
depression: randomised double-blind placebo-controlled study,"
British Journ. Psychiatry, 188, 46-50 (2006). cited by applicant
.
Frey R, Muck W, Kirschbaum N, et al. Riociguat (BAY 63/2521) and
warfarin: a pharmacodynamic and pharmacokinetic interaction study.
J. Clin. Pharmacol. Jul. 2011 51 (7): 1051-60. cited by applicant
.
Frick, MH, et al., "Helsinki Heart Study. Primary prevention trial
with gemfibrozil in middle-aged men with dyslipidaemia. Safety of
treatment, changes in risk factors and incidence of coronary heart
disease", N. Eng. J. Med., 317:1237-1245, (1987). cited by
applicant .
Friedewald, W.T., et al., "Estimation of the concentration of
low-density lipoprotein cholesterol in plasma, without use of the
preparative ultracentrifuge." Clin Chem.,18:499-502 (1972). cited
by applicant .
Friedman, A. N., et al., "Fish Consumption and Omega-3 Fatty Acid
Status and Determinants in Long-Term Hemodialysis." Amer. J. Kidney
Diseases, 47(6):1064-1071 (2006). cited by applicant .
Froyland et al., "Chronic administration of eicosapentaenoic acid
and docosahexaenoic acid as ethyl esters reduced plasma cholesterol
and changed the fatty acid composition in rat blood and organs."
Lipids 31(2):169-78 (Feb. 1996). cited by applicant .
Froyland, L., et al., "Hypotriacylglycerolemic component of fish
oil." Prostaglandins, Leukotrienes and Essential Fatty Acids 57 (4
& 5):387-388 (1997). cited by applicant .
Furuta T, Shirai N, Sugimoto M, et al. Influence of CYP2C19
pharmacogenetic polymorphism on proton pump inhibitor-based
therapies. Drug Metab. Pharmacokinet Jun. 2005 20 (3): 153-67.
cited by applicant .
Futata et al., "Effect of Eicosapentaenoic Acid (EPA) Formulation
on Glucose Metabolism in Non-Insulin Dependent Diabetic Patients,"
Journal of Clinical and Experimental Medicine 169(8):889-890 (May
21, 1994)(English translation, 4 pages). cited by applicant .
Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins
and omega 3 fatty acids on cardiovascular diseases: a randomised
placebo controlled trial. Br Med J. 2010;341:c6273. cited by
applicant .
Galeano NF, Al-Haideri M, Keyserman F, Rumsey SC, Deckelbaum RJ.
Small dense low density lipoprotein has increased affinity for LDL
receptor-independent cell surface binding sites: a potential
mechanism for increased atherogenicity. J. Lipid Res.
1998;39(6):1263-1273. cited by applicant .
Gallagher et al., "Germline BRCA Mutations Denote a
Clinicopathalogic Subset of Prostate Cancer," Amer. Assoc. Cancer
Res. Clin Cancer Res., 16(7):2115-21 (2010). cited by applicant
.
Ganda OP, Bhatt DL, Mason RP, Miller M, Boden WE. Unmet need for
adjunctive dyslipidemia therapy in hypertriglyceridemia management.
J Am Coll Cardiol 72(3):330-43 (publication date Jul. 17, 2018).
cited by applicant .
Garber AJ, Abrahamson MJ, Barzilay JI, et al. American Association
of Clinical Endocrinologists' comprehensive diabetes management
algorithm 2013 consensus statement. Endocr. Pract. 2013;19(suppl
2):1-48. cited by applicant .
Gardner CD, Fortmann SP, Krauss RM. Association of small
low-density lipoprotein particles with the incidence of coronary
artery disease in men and women. JAMA. 1996;276(11):875-881. cited
by applicant .
Garg, R., et al., "Niacin treatment increases plasma homocyst(e)ine
levels", Am. Heart. J., 138:1082-1087, (1999). cited by applicant
.
Garnett, "Interactions with Hydroxymethylglutaryl-coenzyme A
reductase inhibitors," Am J Health-Sys Pharm vol. 52, 1639-1645,
(1995). cited by applicant .
Geleijnse JM, Giltay EJ, Grobbee DE, Donders ART, Kok FJ. Blood
pressure response to fish oil supplementation: metaregression
analysis of randomized trials. J Hypertens. 2002;20(8):1493-1499.
cited by applicant .
Genest, JJ, et al., "Familial lipoprotein disorders in patients
with premature coronary artery disease", 85:2025-2033, (1992).
cited by applicant .
Geppert, et al. "Microalgal docosahexaenoic acid decreases plasma
triacylglycerol in normolipidaemic vegetarians: a randomized
trial." British Journal of Nutrition, 95, 779-786. (2006). cited by
applicant .
Gillet L, Roger S, Bougnoux P, Le Guennec JY, Besson P. Beneficial
effects of omega-3 long-chain fatty acids in breast cancer and
cardiovascular diseases: voltage-gated sodium channels as a common
feature? Biochimi. 2011;93:4-6. cited by applicant .
Gillies, et al. "Effect of a Novel Eicosapentaenoic Acid-Rich Oil
on Serum Cholesterol in Man," DuPont 2010. cited by applicant .
Ginsberg HN, Elam MB, Lovato LC, Crouse JR, 3rd, Leiter LA, Linz P,
Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH,
Ismail-Beigi F, Bigger JT, Goff DC, Jr., Cushman WC, Simons-Morton
DG, Byington RP. Effects of combination lipid therapy in type 2
diabetes mellitus. N. Engl. J. Med. 2010;362:1563-1574. cited by
applicant .
Ginsberg HN, Elam MB, Lovato LC, et al, for the ACCORD Study Group.
Effects of combination lipid therapy in Type 2 diabetes mellitus. N
Engl J Med 362:1563-1574, 2010. cited by applicant .
Ginsberg HN. "Hypertriglyceridemia: new insights and new approaches
to pharmacologic therapy," Am J Cardiol, 87:1174-1180 (2001). cited
by applicant .
Girotti A W. Lipid hydroperoxide generation, turnover, and effector
action in biological systems. J. Lipid Res. 1998;39(8):1529-1542.
cited by applicant .
GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids
in patients with chronic heart failure (the GISSI-HF trial): a
randomised, double-blind, placebo-controlled trial. Lancet.
2008;372(9645):1223-1230. cited by applicant .
GISSI-Prevenzione Investigators, "Dietary Supplementation with n-3
Polyunsaturated Fatty Acids and Vitamin E after Myocardial
Infarction: Results of the GISSI-Prevenzione Trial", The Lancet,
354:447-455, (Aug. 7, 1999). cited by applicant .
Glod, "Recent Advances in the Pharmacotherapy of Major Depression",
Arch. Psychiatr. Nurs., 10(6):355-364 (Dec. 1996). cited by
applicant .
Goff DC, Lloyd-Jones DM, Bennett G, et al. ACC/AHA Prevention
Guideline: 2013 ACC/AHA Guideline on the Assessment of
Cardiovascular Risk: A Report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines. Circulation. 2014;129:S74-S75. cited by applicant .
Goldberg, A C: "Combination therapy of dyslipidemia," Current
Treatment Options in Cardiovascular Medicine 200708 GB, vol. 9, No.
4, pp. 249-258 (2007). cited by applicant .
Goodman & Gilman (Robert W. Mahley & Thomas P. Bersot) Drug
Therapy for Hypercholesterolemia and Dyslipidemia, in Goodman &
Gilman's The Pharmacological Basis fo Therapeutics 971 (Hardman et
al., eds 10th ed. 2001)(32 pages). cited by applicant .
Gordon, DJ. et al., High density lipoprotein cholesterol and
cardiovascular disease: four prospective American studies.
Circulation. 79: 8-15. (1989). cited by applicant .
Gorriz JL et al., "Rhabdomyolysis and Acute Renal Failure
Associated with Gemfibrozil Therapy," Nephron 74(2): 437-438
(1996). cited by applicant .
Gorriz, JL, "Rhabdomyolysis and Acute Renal Failure Associated with
Bezafibrate Treatment," Nephrol Dial Transplant 10(12):2371-2372
(1995). cited by applicant .
Gosai, P. et al. Effect of omega-3-acid ethyl esters on the
steady-state plasma pharmacokinetics of rosuvastatin in healthy
adults. Expert Opin. Pharmacother. 9, 2947-2953 (2008). cited by
applicant .
Goto, Y. et al., "Clinical Pharmacological Trial of Ethyl
Icosapentate (MND-21)-Dose Finding Study." Journal of Clinical
Therapeutic & Medicines 8:1293-309 (1992). cited by applicant
.
Gould, A.L., et al., "Cholesterol reduction yields clinical
benefit: impact of statin trials." Circulation, 97:946-952 (1998).
cited by applicant .
Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs,
natural substances, and foods. J. Clin. Pharmacol. Feb. 2005 45
(2): 127-32. cited by applicant .
Grenyer, Brin F.S., et al., "Fish Oil Supplementation in the
Treatment of Major Depression: A Randomised Double-Blind
Placebo-Controlled Trial", Progress in Neuro-Psychopharmacology
& Biological Psychiatry, 31:1393-1396, (2007). cited by
applicant .
Griffin, M.D., et al., "Effects of altering the ratio of dietary
n-6 to n-3 fatty acids on insulin sensitivity, lipoprotein size,
and postprandial lipemia in men and postmenopausal women aged 45-70
y: the OPTILIP Study." Am J Clin Nutr 84:1290-8 (2006). cited by
applicant .
Grimsgaard et al., "Effects of Highly Purified Eicosapentaenoic
Acid and Docosahexaenoic Acid on Hemodynamics in Humans" American
Society for Clinical Nutrition, 68:52-9, (1998). cited by applicant
.
Grimsgaard, Kaare H. Bonaa, John-Bjarne Hansen, and Arne Nordoy,
"Highly purified eicosapentaenoic acid and docosahexaenoic acid in
humans have similar triacylglycerol-lowering effects but divergent
effects on serum fatty acids" Am J Clin Nutr, 66:649-659, (1997).
cited by applicant .
Grundy S.M et al., Efficacy, safety, and tolerability of once-daily
niacin for the treatment of dyslipidemia associated with type 2
diabetes: results of the Assessment of Diabetes Control and
Evaluation of the Efficacy of Niaspan Trial. Arch. Intern. Med.
162: 1568-1576 (2002). cited by applicant .
Grundy SM, et al. Implications of Recent Clinical Trials for the
National Cholesterol Education Prgram Adult Treatment Panel III
Guidelines, Circulation. 2004; 110:227-39. cited by applicant .
Grundy, Scott M., "Low-Density Lipoprotein, Non-High-Density
Lipoprotein, and Apolipoprotein B as Targets of Lipid-Lowering
Therapy" Circulation. 106:2526-2529 (2002). cited by applicant
.
Guallar, E., et al., "Omega-3 fatty acids in adipose tissue and
risk of myocardial infarction--The EURAMIC study." Arterioscler.
Thromb. Vasc. Biol., 19:1111-1118 (1999). cited by applicant .
Guillot, et al., "Increasing intakes of the long-chain omega-3
docosahexaenoic acid: effects on platelet functions and redox
status in healthy men," The FASEV Journal, vol. 23, pp. 2909-2916
(2009). cited by applicant .
Guizy, M., et al., ".omega.-3 and .omega.-6 Polyunsaturated fatty
acids block HERG channels." Am J Physiol Cell Physiol
289:C1251-C1260 (2005). cited by applicant .
Gyarmathy, M., "Selection from the industrial manufacturing. 5th
part: Gelatine capsules. 5/2 part: Soft gelatine capsules,"
Gyogyszereszet, vol. 38, No. 2, pp. 105-109 (1994) (with English
summary). cited by applicant .
Hakonarson, H., et al., "Effects of a 5-lipoxygenase--activating
protein inhibitor on biomarkers associated with risk of myocardial
infarction--a randomized trial." JAMA, 293(8):2245-56 (2005). cited
by applicant .
Hall, W. L., et al., "A high-fat meal enriched with
eicosapentaenoic acid reduces postprandial arterial stiffness
measured by digital volume pulse analysis in healthy men." J. Nutr.
138: 287-291 (2008). cited by applicant .
Hamazaki et al., "Docosahexaenoic Acid-Rich Fish Oil Does Not
Affect Serum Lipid Concentrations of Normolipidemic Young Adults",
American Institute of Nutrition, 126(11):2784-2789, Nov. 1996.
cited by applicant .
Hamazaki et al., "Effects of Orally Administered Ethyl Ester of
Eicosapentaenoic Acid (EPA: C20:5, omega-3) on PG12-Like Substance
Production by Rat Aorta" Prostaglandins, vol. 23 No. 4, pp. 557-567
(1982). cited by applicant .
Hamazaki T. et al., "Reduction of microalbuminuria in diabetics by
Eicosapentaenoic acid ethyl ester" Lipids. 25 (9):542-5 (1990).
cited by applicant .
Hampel H, Abraham NS, El-Se rag HB. Meta-analysis: obesity and the
risk for gastroesophageal reflux disease and its complications.
Ann. Intern. Med. Aug. 2005 143 (3): 199-211. cited by applicant
.
Han, J. J., et al., "Enhancement of both reaction yield and rate of
synthesis of structured triacylglycerol containing eicosapentaenoic
acid under vacuum with water activity control." Lipids 34:989-995
(1999). cited by applicant .
Hanasaki, K., et al., "Potent modification of low density
lipoprotein by group X secretory phospholipase A2 is linked to
macrophage foam cell formation." J. Biol. Chem. 277(32):29116-24
(2002). cited by applicant .
Haney, E.M., et al., "Screening for lipid disorders in children and
adolescents; Systematic evidence review for the U.S. Preventive
Services Task Force (evidence synthesis)." No. 47. Rockville, MD:
Agency for Healthcare Research and Quality, US Department of Health
and Human Services; AHRQ Publication No. 07-0598-EF-1; Jul. 2007.
Available at:
http://www.uspreventiveservicestaskforce.org/uspstf07/chlipid/chlipidsyn.-
pdf. (Accessed Mar. 23, 2011)(573 pages). cited by applicant .
Hannah, J., et al., "Effect of dietary fatty acids on LDL binding."
Ann N Y Acad Sci., 683:178-182 (1993). cited by applicant .
Hansen et al., "Comparative effects of prolonged intake of highly
purified fish oils as ethyl ester ortriglyceride on lipids,
haemostasis and platelet function in normolipaemic men." Eur. J.
Clin. Nutr. 47(7):497-507 (Jul. 1993). cited by applicant .
Hansen, J.B., et al., "Effects of highly purified eicosapentaenoic
acid and docosahexaenoic acid on fatty acid absorption,
incorporation into serum phospholipids and postprandial
triglyeridemia." Lipids 33:131-38 (1998). cited by applicant .
Harada-Shiba et al., Journal of Clinical and Experimental Medicine,
Jun. 30, 2007, vol. 221, No. 13, pp. 1068-1073 (with English
translation). cited by applicant .
Harris WS. International recommendations for consumption of
long-chain omega-3 fatty acids. J Cardiovasc Med (Hagerstown)
8(suppl 1):S50-S52, 2007. cited by applicant .
Harris, "n-3 Fatty acids and lipoproteins: a comparison of results
from human and animal studies," Lipids 31, 243-252 (1996). cited by
applicant .
Harris, W. S. et al. "Safety and efficacy of Omacor in severe
hypertriglyceridemia," Journal of Cardiovascular Risk, 4:385-391
(1997). cited by applicant .
Harris, W. S., "Fish oils and plasma lipid and lipoprotein
metabolism in humans: a critical review." J Lipid Res. 30:785-807
(1989). cited by applicant .
Harris, W. S., "The omega-3 index as a risk factor for coronary
heart disease." Am J Clin Nutr 87:1997S-2002S (2008). cited by
applicant .
Harris, W. S., et al., "n-3 Fatty acids and urinary excretion of
nitric oxide metabolites in humans." Am. J. Clin. Nutr., 65:459-64
(1997). cited by applicant .
Harris, W. S. et al "Influence of n-3 fatty acid supplementation on
the endogenous activities of plasma lipases." Am. J. Clin. Nutr.
66:254-60 (1997). cited by applicant .
Harris, W.S., "Expert opinion: omega-3 fatty acids and
bleeding-cause for concern?" The American Journal of Cardiology
99(6A): 45C-46C (2007). cited by applicant .
Harris, W.S., "n-3 Fatty acids and human lipoprotein metabolism: an
update." Lipids 34:S257-S258 (1999). cited by applicant .
Harris, W.S., "n-3 Fatty acids and serum lipoproteins: human
studies." Am J Clin Nutr 65:1645S-54S (1997). cited by applicant
.
Harris, W.S.: "Omega-3 fatty acids in cardiac biopsies from heart
transplantation patients." Circulation 110;1645-1649 (2004). cited
by applicant .
Harris, W.S., et al., "Comparison of the effects of fish and
fish-oil capsules on the n-3 fatty acid content of blood cells and
plasma phospholipids." Am J Clin Nutr 86:1621-5 (2007). cited by
applicant .
Harris, W.S., et al., "Omega-3 fatty acids and coronary heart
disease risk: Clinical and mechanistic perspectives."
Atherosclerosis 197:12-24 (2008). cited by applicant .
Harris, W.S., et al., "Stearidonic acid increases the red blood
cell and heart eicosagentaenoic acid content in dogs." Ligids
42:325-333 (2007). cited by applicant .
Harris, W.S., et al., "Tissue n-3 and n-6 fatty acids and risk for
coronary heart disease events." Atherosclerosis 193:1-10 (2007).
cited by applicant .
Hartweg, J., et al., "Potential impact of omega-3 treatment on
cardiovascular disease in type 2 diabetes." Curr Opin Lipidol.,
20:30-38 (2009). cited by applicant .
Hata et al, Geriatric Medicine, 30 (5), 799-852, 1992 (with English
introduction). cited by applicant .
Hawthorne, et al., "High dose eicosapentaenoic acid ethyl ester:
effects on lipids and neutrophil leukotriene production in normal
volunteers." Br. J. Clin. Pharmac., vol. 30, 187-194 (1990). cited
by applicant .
Hayashi et al., Decreases in Plasma Lipid Content and Thrombotic
Activity by Ethyl Icosapentate Purified from Fish Oiles, Current
Therapeutic Research, vol. 56, No. 1, pp. 24-31 (1995). cited by
applicant .
Herbette L, Marquardt J, Scarpa A, Blasie JK. A direct analysis of
lamellar x-ray diffraction from hydrated oriented multilayers of
fully functional sarcoplasmic reticulum. Biophys. J.
1977;20(2):245-272. cited by applicant .
Hibbeln, J. R., et al., "Healthy intakes of n-3 and n-6 fatty
acids: estimations considering worldwide diversity." Am J Clin
Nutr. 83:1483S-93S (2006). cited by applicant .
Higashihara et al. "Effects of Eicosapentaenoic Acid on Biochemical
Failure after Radical Prostatectomy for Prostate Cancer," in vivo
24:561-566 (2010). cited by applicant .
Hilpert, K.F., et al., "Postprandial effect of n-3 polyunsaturated
fatty acids on apolipoprotein B-containing lipoproteins and
vascular reactivity in type 2 diabetes." Am J Clin Nutr 85:369-76
(2007). cited by applicant .
Hirafuji, M., et al., "Docosahexaenoic acid potentiates
interleukin-1beta induction of nitric oxide synthase through
mechanism involving p44/42 MAPK activation in rat vascular smooth
muscle cells." British Journal of Pharmacology 136:613-619 (2002).
cited by applicant .
Hirai, A., et al., "The effects of the oral administration of fish
oil concentrate on the release and the metabolism of [14C ]
arachidonic acid and [14C ] eicosapentaenoic acid by human
platelets", Thromb. Res., 28:285-298, (1982). cited by applicant
.
Hirano T, Ito Y, Koba S, Toyoda M, Ikejiri A, Saegusa H, Yamazaki
J, Yoshino G. Clinical significance of small dense low-density
lipoprotein cholesterol levels determined by the simple
precipitation method. Arterioscler. Thromb. Vase. Biol.
2004;24(3):558-563. cited by applicant .
Hirano, R., et al., "Regulation by long-chain fatty acids of the
expression of cholesteryl ester transfer protein in HepG2 cells."
Lipids, 36:401-406 (2001). cited by applicant .
Hofacer R, et al., Omega-3 fatty acid deficiency increases
stearoyl-CoA desaturase expression and activity indices in rat
liver: Positive association with non-fasting plasma triglyceride
levels, Prostaglandins Leukot. Essent. Fatty Acids. 2012;86:71-7.
cited by applicant .
Hoffman, "Atherosclerosis: Prevention through the Ages," WebMD,
https://www.webmed.com/heart/features/atherosclerosis-prevention-through--
ages#1, (Dec. 4, 2007). cited by applicant .
Hohenester, "Primary Biliary Cirrhosis," Semin Immunopathol.
31L:283-307, 285 (2009). cited by applicant .
Holmeide, A. K., et al., "Oxidative degradation of eicosapentaenoic
acid into polyunsaturated aldehydes." Tetrahedron 59:7157-7162
(2003). cited by applicant .
Holub, B.J., PhD, "Fish Oils and Cardiovascular Disease", Canadian
Medical Association Journal, 141(10):1063 (1989). cited by
applicant .
Holvoet P, Kritchevsky SB, Tracy RP, Mertens A, Rubin SM, Butler J,
Goodpaster B, Harris TB. The metabolic syndrome, circulating
oxidized LDL, and risk of myocardial infarction in wellfunctioning
elderly people in the health, aging, and body composition cohort.
Diabetes. 2004;53(4):1068-1073. cited by applicant .
Hom et al., "Soft Gelatin Capsules II: Oxygen Permeability Study of
Capsule Shells," J Pharm Sci. (1975) 64(5):851-857. cited by
applicant .
Hombeck, M., et al., "Biosynthesis of the algal pheromone
fucoserratene by the freshwater diatom Asterionella formosa
(Bacillariophyceae)." Tetrahedron 54:11033-11042 (1998). cited by
applicant .
Hong KN, Fuster V, Rosenson RS, Rosendorff C, Bhatt DL. How low to
go with glucose, cholesterol, and blood pressure in primary
prevention of CVD. J Am Coll Cardiol 70(17):2171-85 (publication
date Oct. 24, 2017; epublication date Oct. 16, 2017). cited by
applicant .
Hoogeveen EK, Geleijnse JM, Kromhout D, et al. No effect of n-3
fatty acids supplementation on NT-proBNP after myocardial
infarction: the Alpha Omega Trial. Eur J Prey Cardiol. May
2015;22:648-55. cited by applicant .
Horrobin, D.F. The Phospholipid Concept of Psychiatric Disorders
and its Relationship to the Neurodevelopmental Concept of
Schizophrenia. In M. Peet (ed.) Phospholipid Spectrum Disorder in
Psychiatry pp. 1-19 (1999). cited by applicant .
Hoskins et al., "Combination use of statins and omega-3 fatty
acids: an emerging therapy for combined hyperlipidemia," Abstract,
1(5): 579-591(13) (2006). cited by applicant .
Howe, P.R.C., et al., "Equal antithrombotic and
triglyceride-lowering effectiveness of eicosapentaenoic acid-rich
and docosahexaenoic acid-rich fish oil supplements." Lipids
34:S307-S308 (1999). cited by applicant .
HPs2-thrive Collaborative Group, "randomized placebo-controlled
trial in 25 673 high-risk patients of er niacin/laroprant: Trial
design, pre-specified muscle and liver outcomes, and reasons for
stopping study treatment." Eur. Heart J. 2013;34:1279-1291. cited
by applicant .
HPS2-Thrive Collaborative Group, Landray MJ, Haynes R, et al.
Effects of extended-release niacin with laropiprant in high-risk
patients. N Engl J Med. 2014;371(3):203-12. cited by applicant
.
Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, Frye
RF. The effect of trimethoprim on CYP2C8 mediated rosiglitazone
metabolism in human liver microsomes and healthy subjects. Br. J.
Clin. Pharmacol. 2005;59:70-79. cited by applicant .
Hughes et al., "Fish oil produces an atherogenic lipid profile in
hypertensive men," Atherosclerosis, 84, pp. 229-237 (1990). cited
by applicant .
Hulthe J, Hulten LM, Fagerberg B. Low adipocyte-derived plasma
protein adiponectin CJ concentrations are associated with the
metabolic syndrome and small dense low-density lipoprotein
particles: atherosclerosis and insulin resistance study. Metab.
Clin. Exp. 2003;52(12):1612-1614. cited by applicant .
Huntington's Diesase Drug Works--The DHA Dilemma
http://hddrugworks.org/index2.php?option=com_content&task=view&id=185&pop-
=1&pa . . . Printed on Aug. 22, 2008.(2 pages). cited by
applicant .
Ignarro LJ, Buga GM, Wood KS, Byrnes RE, Chaudhuri G.
Endothelium-derived relaxing factor produced and released from
artery and vein is nitric oxide. Proc. Natl. Acad. Sci. USA.
1987;84:9265-9269. cited by applicant .
Illingworth, DR, et al., "Comparative effects of lovastatin and
niacin in primary hypercholesterolemia: A prospective trial", Arch.
Int. Med., 154:1586-1595, (1994). cited by applicant .
Inoue, I., et al., "Expression of peroxisome proliferator-activated
receptor .alpha. (PPAR.alpha.) in primary cultures of human
vascular endothelial cells." Biochem. Biophys. Res. Comm., 246,
370-374 (1998). cited by applicant .
Inzucchi et al., "Diagnosis of Diabetes," New Engl. Journ of Med.,
367(6):541-550 (2012). cited by applicant .
Ishida, Y., et al., ".alpha.-Lipoic Acid and Insulin Autoimmune
Syndrome." Diabeters Care, 30(9): 2240-41 (2007). cited by
applicant .
Isley, et al., "Pilot study of combined therapy with .omega.-3
fatty acids and niacin in atherogenic dyslipidemia," Journal of
Clinical Lipidology, 1, 211-217 (2007). cited by applicant .
Itoh et al., "Increased adinponectin secretion by highly purified
eicosapentaenoic acid in rodent models of obesity and human obses
subjects," Arterioscler. Thromb. Vasc. Biol., pp. 1918-1925
(together with online Sugglements 1-15) (2007). cited by applicant
.
Jacob RF, Mason RP. Lipid peroxidation induces cholesterol domain
formation in model membranes. J. Biol. Chem.
2005;280(47):39380-39387. cited by applicant .
Jacob RF, Walter MF, Self-Medlin Y, Mason RP. Atorvastatin active
metabolite inhibits oxidative modification of small dense
low-density lipoprotein. J. Cardiovasc. Pharmacol.
2013;62(2):160-166. cited by applicant .
Jacobson et al. "Hypertriglyceridemia and Cardiovascular Risk
Reduction", Clinical Therapeutics, vol. 29 pp. 763-777 (2007).
cited by applicant .
Jacobson TA. Opening a new lipid "apo-thecary": incorporating
apolipoproteins as potential risk factors and treatment targets to
reduce cardiovascular risk. Mayo Clin. Proc. 2011;86:762-780. cited
by applicant .
Jacobson, T. Secondary Prevention of Coronary Artery Disease with
Omega-3 Fatty Acids. Am J Cardiol; 98 [suppl]: 61i-70i (2006).
cited by applicant .
Jacobson, T.A., "Role of n-3 fatty acids in the treatment of
hypertriglyceridemia and cardiovascular disease." Am J Clin Nutr
87:1981S-90S (2008). cited by applicant .
Jacobson, T.A., et al., "Effects of eicosapentaenoic acid and
docosahexaenoic acid on low-density lipoprotein cholesterol and
other lipids: A review." J. Clin. Lipidology, vol. 6, pp. 5-18
(2012). cited by applicant .
Jakus V, Rietbrock N. Advanced glycation end-products and the
progress of diabetic vascular complications. Physiol. Res.
2004;53(2): 131-142. cited by applicant .
Jenner, "Presymptomatic Detection of Parkinson's Disease". J Neural
Transm Suppl., 40:23-36. (Abstract only) (1993). cited by applicant
.
Jialal I, Devaraj S. Antioxidants and atherosclerosis: Don't throw
out the baby with the bath water. Circulation. 2003;107:926-928.
cited by applicant .
Jialal, I. "Editorial: Remnant lipoproteins: measurement and
clinical significance." Clinical Chemistry 48(2):217-219 (2002).
cited by applicant .
Jinno Y, Nakakuki M, Kawano H, Notsu T, Mizuguchi K, Imada K.
Eicosapentaenoic acid administration attenuates the
pro-inflammatory properties of VLDL by decreasing its
susceptibility to lipoprotein lipase in macrophages. Atheroscler.
2011;219:566-572. cited by applicant .
Jong et al., "Role of ApoCs in Lipoprotein Metabolism: Function
Differences Between ApoC1, ApoC2, and ApoC3," Arteriosclerosis,
Thrombosis and Vascular Biology. (1999) 19(3):472-484. cited by
applicant .
Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybj.ae
butted.rg-Hansen A. Loss-of-function mutations in APOC3 and risk of
ischemic vascular disease. N Engl J Med. 2014; 371 (1):32-41. cited
by applicant .
Journal of Practical Pharmacy, "Hyperlipidemia Drug,"
58(4):1303-1324 (2007) (with English abstract). cited by applicant
.
Journal of the Japan Diabetes Society, "The Relationship Between
Postprandial ApoB48 Increase and Insulin Resistance in Type-2
Diabetes," 55(Suppl. 1):S310 (Apr. 2012) (with English
Translation)(5 pages). cited by applicant .
Journal of the Japanese Diabetes Society, "A Case of Familial
Combined Hyperlipidemia Associated with Obesity, Type 2 Diabetes
Mellitus and Severe Hypertriglyceridemia," 51(3), pp. 233-237 (Mar.
30, 2008) (with English abstract). cited by applicant .
Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular
outcomes: a systematic review and meta-analysis. Lancet 375
(9729):1875-1884, 2010. cited by applicant .
Jung, U.J. et al., "n-3 Fatty acids and cardiovascular disease:
mechanisms underlying beneficial effects." Am J Clin Nutr 87:
2003S-9S (2008). cited by applicant .
Kamanna et al., "Mechanism of Action of Niacin," The American
Journal of Cardiology (Apr. 17, 2008), 101(8), S20-S26. cited by
applicant .
Kamido et al., Lipid Composition of Platelets from Patients with
Atherosclerosis:Effect of Purified Eicosapentaenoic Acid Ethyl
Ester Administration, 1988, Lipids, 23, pp. 917-923 [Abstract only]
(7 pages). cited by applicant .
Kaminski WE, Jendraschak E, Kiefl R, et al. Dietary omega-3 fatty
acids lower levels of platelet-derived growth factor mRNA in human
mononuclear cells. Blood Apr. 1993 81 (7): 1871-9. cited by
applicant .
Kanayasu, T., et al., "Eicosapentaenoic acid inhibits tube
formation of vascular endothelial cells in vitro." Lipids
26:271-276 (1991). cited by applicant .
Kastelein et al., Omega-3 Free Fatty Acids for the Treatment of
Severe Hypertriglyceridemia: The EpanoVa for Lowering Very High
Triglycerides (EVOLVE) Trial, J. Clin. Lipidol. (JACL 597) 2013 (54
pages). cited by applicant .
Katan, M. B., et al., "Kinetics of the incorporation of dietary
fatty acids into serum cholesteryl esters, erythrocyte membranes,
and adipose tissue: an 18-month controlled study." J. Lipid Res.
38: 2012-2022 (1997). cited by applicant .
Katayama et al., Effect of long-term administration of ethyl
eicosapentate (EPA-E) on local cerebral blood flow and glucose
utilization in stroke-prone spontaneously hypertensive rats
(SHRSP), Brain Research, vol. 761, pp. 300-305 (Dec. 31, 1997).
cited by applicant .
Katayama et al., "Efficacy and Safety of Ethyl Icosapentate
(Epadel) Given for a Long Term Against Hyperlipidemia," Prog. Med.,
21:457-467 (2001) (with English translation). cited by applicant
.
Kato, T., et al., "Palmitate impairs and eicosapentaenoate restores
insulin secretion through regulation of SREBP-1c in pancreatic
islets." Diabetes, 57(9):2382-2392 (2008) (published online May 5,
2008.). cited by applicant .
Kawamura et al., "Effects of 4 weeks' intake of polyunsaturated
fatty acid ethylester rich in eicosapentaenoic acid (ethylester) on
plasma lipids, plasma and platelet phsopholipid fatty acid
composition and platelet aggregation; a double blind study," Nihon
Naika Gakkai Zasshi, 72(1):18-24 (1983). cited by applicant .
Kawano, H., et al., "Changes in aspects such as the collagenous
fiber density and foam cell size of atherosclerotic lesions
composed of foam cells, smooth muscle cells and fibrous components
in rabbits caused by all-cis 5, 8, 11, 14, 17-icosapentaenoic
acid", J. Atheroscler. Thromb., 9:170-177, (2002). cited by
applicant .
Kawashima, H., et al., "Oral Administration of
Dihomo-.gamma.-Linolenic Acid Prevents Development of Atopic
Dermatitis in NC/Nga Mice." Lipids 43:37-43 (2008). cited by
applicant .
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder
P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi Y A, Sullivan
D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M.
Effects of long-term fenofibrate therapy on cardiovascular events
in 9795 people with type 2 diabetes mellitus (the FIELD study):
Randomised controlled trial. Lancet. 2005;366:1849-1861. cited by
applicant .
Kelley, D. S., et al., "Docosahexaenoic Acid Supplementation
Decreases Remnant-Like Particle-Cholesterol and Increases the (n-3)
Index in Hypertriglyceridemic Men." J. Nutr. 138: 30-35 (2008).
cited by applicant .
Kelley, et al., "Docosahexaenoic acid supplementation improves
fasting and postprandial lip profiles in hypertriglyceridemic men."
The American Journal of Clinical Nutrition, 86: 324-333 (2007).
cited by applicant .
Kellner-Weibel G, Yancey PG, Jerome WG, Walser T, Mason RP,
Phillips MC, Rothblat GH. Crystallization of free cholesterol in
model macrophage foam cells. Arterioscler. Thromb. Vasc. Biol.
1999;19(8):1891-1898. cited by applicant .
Kendall BJ, Macdonald GA, Hayward NK, et al. The risk of Barrett's
esophagus associated with abdominal obesity in males and females.
Int. J. Cancer May 2013 132 (9): 2192-9. cited by applicant .
Kerr, S., Brosnan MJ, Mcintyre M, Reid JL, Dominiczak AF, Hamilton
CA. Superoxide anion production is increased in a model of genetic
hypertension role of the endothelium. Hypertension.
1999;33:1353-1358. cited by applicant .
Kew, S., et al., "Effects of oils rich in eicosapentaenoic and
docosahexaenoic acids on immune cell composition and function in
healthy humans." Am J Clin Nutr 79:674-81 (2004). cited by
applicant .
Kholodov et al., "Clinical Pharmacokinetics," M. Medicine. (1985)
pp. 89-98, 134-138, 160, 378-380 [with English Summary](27 pages).
cited by applicant .
Khoueiry G, Rafeh NA, Sullivan E, et al. Do omega-3 polyunsaturated
fatty acids reduce risk of sudden cardiac death and ventricular
arrhythmias? A meta-analysis of randomized trials. Heart and Lung.
2013;42:251-256. cited by applicant .
Kim F, Tysseling KA, Rice J, Gallis B, Haji L, Giachelli CM, Raines
EW, Corson MA, Schwartz MW. Activation of IKKbeta by glucose is
necessary and sufficient to impair insulin signaling and nitric
oxide production in endothelial cells. J. Mol. Cell. Cardiol.
2005;39(2):327-334. cited by applicant .
Kim KA, Park PW, Kim HK, Ha JM, Park JY. Effect of quercetin on the
pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in healthy
subjects. J. Clin. Pharmacol. 2005;45:941-946. cited by applicant
.
Kimura, F., et al., "Long-term supplementation of docosahexaenoic
acid-rich, eicosapentaenoic acid-free microalgal oil in n-3 fatty
acid-deficient rat pups." Biosci. Biotechnol. Biochem.,
72(2):608-610 (2008). cited by applicant .
Kinoshita, "Anti-hyperlipidemic agents," Nihon Rinsho, 60(5):968-74
(May 2002) (with English Abstract)(11 pages). cited by applicant
.
Kinsella, J.E., et al., "Dietary n-3 polyunsaturated fatty acids
and amelioration of cardiovascular disease: possible mechanisms."
Am J Clin Nutr 52:1-28 (1990). cited by applicant .
Kitada, 9th Diabetes Drug and Drug Related Seminar Diabetes
Q&A, Kanazawa Medical University, Diabetes and Endocrine
Internal Medicine
(http://plaza.umin.ac.jp/iby/etcdata/yakuyaku110410.pdf)(Apr. 10,
2011) (with English translation)(105 pages). cited by applicant
.
Klempfner R, Erez A, Sagit BZ, et al. Elevated triglyceride level
is independently associated with increased all-cause mortality in
patients with established coronary heart disease: Twenty-two-year
follow-up of the Bezafibrate Infarction Prevention Study and
Registry. Circ Cardiovasc Qual Outcomes 9(2):100-8 (publication
date Mar. 8, 2016). cited by applicant .
Knapp HR. Dietary fatty acids in human thrombosis and hemostasis.
Am. J. Clin. Nutr. May 1997 65 (5 Suppl): 1687S-98S. cited by
applicant .
Knopp, R.H., et al., "Contrasting effects of unmodified and
time-release forms of niacin on lipoproteins in hyperlipidemic
subjects: clues to mechanism of action of niacin", Metabolism,
34:642-650, (1985). cited by applicant .
Koba S, Hirano T, Ito Y, Tsunoda F, Yokota Y, Ban Y, Iso Y, Suzuki
H, Katagiri T. Significance of small dense low-density
lipoprotein-cholesterol concentrations in relation to the severity
of coronary heart diseases. Atherosclerosis. 2006;189(1):206-214.
cited by applicant .
Kohno, M., et al., "Inhibition by Eicosapentaenoic Acid of
Oxidized-LDL- and Lysophosphatidylcholine-Induced Human Coronary
Artery Smooth Muscle Cell Production of Endothelin." J. Vasc. Res.
38:379-388 (2001). cited by applicant .
Kojda G, Harrison DG. Interactions between no and reactive oxygen
species: Pathophysiological importance in atherosclerosis,
hypertension, diabetes and heart failure. Cardiovasc. Res.
1999;43:562-571. cited by applicant .
Kojima, T, et al., "Long-term administration of highly purified
eicosapentaenoic acid provides improvement of psoriasis."
Dermatologica, 182:225-230 (1991). cited by applicant .
Koroshetz, W.J. Huntington's Disease. In Samuels, M. (ed.) Office
Practice of Neurology, pp. 654-661 (1996). cited by applicant .
Kosonen, O., et al., "Inhibition by nitric oxide-releasing
compounds of E-selectin expression in and neutrophil adhesion to
human endothelial cells." European Journal of Pharmacology
394:149-156 (2000). cited by applicant .
Koyama et al., Plaque Reduction and Stabilization Observed in
Borderline Diabetes Using Coronary CT Angiogram During
Administration of Purified Eicosapentaenoic Acid (EPA) Ther. Res.
31(2):219-225 (Feb. 2010) (with English translation)(20 pages).
cited by applicant .
Krauss RM. Heterogeneity of plasma low-density lipoproteins and
atherosclerosis risk. Curr. Opin. Lipidol. 1994;5(5):339-349. cited
by applicant .
Kris-Etherton, et al., "Fish Consumption, Fish Oil, Omega-3 Fatty
Acids, and Cardiovascular Disease" Circulation, 106:2747-2757
(2002). cited by applicant .
Kris-Etherton, P. M., et al., "Omega-3 Fatty Acids and
Cardiovascular Disease--New Recommendations From the American Heart
Association." Arterioscler Thromb Vasc Biol. 23:151-152 (2003).
cited by applicant .
Krzynowek et al., "Purification of Omega-3 Fatty Acids from Fish
Oils Using HPLC: An Overview," National Marine
Fisheries--Proceedings of the first joint conference of the
Tropical and Subtropical Fisheries Technological Soceity of the
Americas with the Atlantic Fisheries Technological Society, pp.
74-77 (1988). cited by applicant .
Ku, K., et al., "Beneficial Effects of to-3 Fatty Acid Treatment on
the Recovery of Cardiac Function After Cold Storage of
Hyperlipidemic Rats." Metabolism, 48(10):123-1209 (1999). cited by
applicant .
Kunimoto M, Inoue K, Nojima S. Effect of ferrous ion and
ascorbate-induced lipid peroxidation on liposomal membranes.
Biochem. BioghysActa. 1981;646(1):169-178. cited by applicant .
Kurabayashi, T., et al., "Eicosapentaenoic acid effect on
hyperlipidemia in menopausal Japanese women." Obstet Gynecol
96:521-8 (2000). cited by applicant .
Labor Diagnostik Karlsruhe, "Target Values of Lipid Metabolism
[Recommendation for lipid plasma levels in Germany]," (exact
publication date unknown; circa 2006) (with English abstract)(4
pages). cited by applicant .
Lada et al., "Associations of Low Density Lipoprotein Particle
Compositions with Atherogenicity," Curr. Opin. Lipidol. (2004)
15(1):19-24. cited by applicant .
Lai, E. et al "Suppression of niacin-induced vasodilation with an
antagonist to prostaglandin D2 receptor subtype 1", Clin. Pharm.
& Ther., 81:849-857, (2007). cited by applicant .
Laidlaw, M., et al., "Effects of supplementation with fish
oil-derived n-3 fatty acids and .gamma.-linolenic acid on
circulating plasma lipids and fatty acid profiles in women." Am J
Clin Nutr 77:37-42 (2003). cited by applicant .
Laird et al., "Relationship of early hyperglcemia to mortality in
trauma patients," J. Trauma, 56(5):1058-1062 (May 2004). cited by
applicant .
Lamb RE, Goldstein BJ. Modulating an Oxidative-Inflammatory
Cascade: Potential New Treatment Strategy for Improving Glucose
Metabolism, Insulin Resistance, and Vascular Function. Int. J.
Clin. Pract. 2008;62(7): 1087-1095. cited by applicant .
Lamharzi N, Renard CB, Kramer F, Pennathur S, Heinecke JW, Chait A,
Bomfeldt KE. Hyperlipidemia in concert with hyperglycemia
stimulates the proliferation of macrophages in atherosclerotic
lesions: potential role of glucose-oxidized LDL. Diabetes.
2004;53(12):3217-3225. cited by applicant .
Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM,
Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to
uncoupling of endothelial cell nitric oxide synthase in
hypertension. J. Clin. Invest. 2003;111:1201-1209. cited by
applicant .
LaRosa JC. Understanding risk in hypercholesterolemia. Clin Cardiol
26(Suppl 1):3-6, 2003. cited by applicant .
Larsen, L.N., et al., "Heneicosapentaenoate (21:5n-3): Its
incorporation into lipids and its effects on arachidonic acid and
eicosanoid Synthesis." Lipids 32:707-714 (1997). cited by applicant
.
Laufs et al., "Upregulation of endothelial nitric oxide synthase by
hmg coa reductase inhibitors," Circulation (1998) 97:1129-1135.
cited by applicant .
Law TK, Yan AT, Gupta A, et al. Primary prevention of
cardiovascular disease: global cardiovascular risk assessment and
management in clinical practice. Eur Heart J Qual Care Clin
Outcomes. 1(1):31-36 (publication date Jul. 2, 2015; epublication
date Jul. 1, 2015). cited by applicant .
Law, M.R., et al., "Quantifying effect of statins on low density
lipoprotein cholesterol, ischaemic heart disease, and stroke:
systematic review and meta-analysis." Br Med J., 326:1423-1427
(2003). cited by applicant .
Lawson et al., "Human absorption of fish oil fatty acids as
triacylglycerols, free acids or ethyl esters," Biochemical and
Biophysical Research Communications 152(1):328-335 (Apr. 15, 1988).
cited by applicant .
Leaf A, Albert CM, Josephson M, et al. for the Fatty Acid
Antiarrhythmia Trial Investigators. Prevention of Fatal Arrhythmias
in High-Risk Subjects by Fish Oil n-3 Fatty Acid Intake. Circ.
2005;112:2762-2768. cited by applicant .
Leaf A, Kang JX. Prevention of cardiac sudden death by N-3 fatty
acids: a review of the evidence. J Intern Med 240:5-12, 1996. cited
by applicant .
Leaf, "Hypertriglyceridemia: A Guide to Assessment and Treatment,"
Hospital Physician 17-23 (Sep. 2008). cited by applicant .
Leaf, A., "Historical overview of n3 fatty acids and coronary heart
disease." Am J Clin Nutr 87:1978S-80S. (2008). cited by applicant
.
Lee and G.Y.H. Lip, "The Role of Omega-3 Fatty Acids in the
Secondary Prevention of Cardiovascular Disease", Q J Med,
96:465-480, (2003). cited by applicant .
Lee C, Sigari F, Segrado T, Horkko S, Hama S, Subbaiah PV, Miwa M,
Navab M, Witztum JL, Reaven PD. All ApoB-containing lipoproteins
induce monocyte chemotaxis and adhesion when minimally modified.
Modulation of lipoprotein bioactivity by platelet-activating factor
acetylhydrolase. Arterioscler. Thromb. Vase. Biol. 1999; 19(6):
1437-1446. cited by applicant .
Lee, J.H., et al., "Omega-3 fatty acids for cardioprotection." Mayo
Clin Proc., 83(3):324-332 (2008). cited by applicant .
Leigh-Firbank et al., "Eicosapentaenoic acid and docosahexanoic
acid from fish oils: differential associations with lipid
responses," Br. J. Nutr. 87:435-445 (2002). cited by applicant
.
Lemaitre, R.N., et al., "n-3 Polyunsaturated fatty acids, fatal
ischemic heart disease, and nonfatal myocardial infarction in older
adults: the Cardiovascular Health Study." Am J Clin Nutr 77:319-25
(2003). cited by applicant .
Leonard, Brian E., "Neurological Aspects", Fundamentals of
Psychopharmacology,186-187, (1997). cited by applicant .
Leucht, S., et al., Schizophrenia Research, vol. 35, "Efficacy and
extrapyramidal side-effects of the new antipsychotics olanzapine,
quetiapine, risperidone, and sertindole compared to conventional
antipsychotics and placebo. A meta-analysis of randomized
controlled trials", pp. 51-68, (1999). cited by applicant .
Levey A, at. al. A New Equation to Estimate Glomerular Filtration
Rate. Ann Intern Med. 150:604-612; 2009. cited by applicant .
Li, D. et al., "Effect of dietary a-linolenic acid on thrombotic
risk factors in vegetarian men." Am J Clin Nutr 69:872-82 (1999).
cited by applicant .
Li, H. et al., "EPA and DHA reduce LPS-induced inflammation
responses in HK-2 cells: Evidence for a PPAR-.gamma.-dependent
mechanism." Kidney Int'l. 67:867-74 (2005). cited by applicant
.
Libby P. Triglycerides on the rise: should we swap seats on the
seesaw? Eur Heart J. 36(13):774-776 (publication date Apr. 1, 2015;
epublication date Dec. 29, 2014). cited by applicant .
Libby, "Inflammation and atherosclerosis," Nature (2002)
420(6917):868-874. cited by applicant .
Lichtman et al., "Depression and Coronary Heart Disease,
Recommendations for Screening, Referral and Treatment," AHA Science
Advisory, Circulation 118:1768-1775 (Sep. 29, 2008). cited by
applicant .
Lien, E.L., "Toxicology and safety of DHA." Prostaglandins Leukot
Essent Fatty Acids., 81:125-132 (2009). cited by applicant .
Lin, Pao-Yen, M.D., et al., "A Meta-Analytic Review of
Double-Blind, Placebo-Controlled Trials of Antidepressant Efficacy
of Omega-3 Fatty Acids", Psychiatry, 1056-1061 (Jul. 2007). cited
by applicant .
Lin, Y., et al., "Differential effects of eicosapentaenoic acid on
glycerolipid and apolipoprotein B metabolism in primary human
hepatocytes compared to HepG2 cells and primary rat hepatocytes."
Biochimica et Biophysica Acta 1256:88-96 (1995). cited by applicant
.
Lindsey, S., et al., "Low density lipoprotein from humans
supplemented with n-3 fatty acids depresses both LDL receptor
activity and LDLr mRNA abundance in HepG2 cells." J Lipid Res.,
33:647-658 (1992). cited by applicant .
Lipitor [package insert]. New York, NY: Parke-Davis (2012). (22
pages). cited by applicant .
Lipitor [product information] Dublin, Ireland: Pfizer Inc. (
2007).(18 pages). cited by applicant .
Liu et al., "Effects of stable fish oil and simvastatin on plasma
lipoproteinc in patients with hyperlipidemia," Nutrion Res. , vol.
23, pp. 1027-1034 (2003). cited by applicant .
Liu X, et al., Stearoyl CoA Desaturase 1: Role in Cellular
Inflammation and Stress, Adv. Nutr. 2011;2:15-22. cited by
applicant .
Lohmussaar, E., et al., "ALOX5AP Gene and the PDE4D Gene in a
Central European Population of Stroke Patients." Stroke, 36:731-736
(2005). cited by applicant .
Lovaza (omega-3-acid ethyl esters) Capsules, Prescribing
information, GlaxoSmithKline (Nov. 2008).(9 pages). cited by
applicant .
Lovaza [package insert]. Research Triangle Park, NC:
GlaxoSmithKline (2012). (14 pages). cited by applicant .
Lovaza Side Effects, web archived webpage, archived from Drugs.com
website on (Jul. 31, 2010), Retrieved from URL
<https://web.archive.org/web/20100731021902/https://www.drugs.com/sfx/-
lovaza-side-effects.html> (4 pages)(Jul. 2010). cited by
applicant .
Lovaza United States Prescribing Information, GlaxoSmithKline.
Research Triangle Park, USA, May 2014. cited by applicant .
Lovaza, (omega-3-acid ethyl esters) Capsules, Prescribing
information Smith Kline Beechum (Jul. 2009).(17 pages). cited by
applicant .
Lovaza, GlaxoSmithKline, Lovaza Prescribing Information, Jun. 2008
[retrieved from the internet Jun. 6, 2012
<https://web.archive.org/web/20090206170311/http://us.gsk.com/products-
/assets/us_lovaza.pdf>]; Table 3, p. 1, section entitled
`Description;` p. 3, section entitled `Very High Triglycerides:
Monotherapy;` p. 4 section entitled `Indications and Usage` and
`Information for Patients.` (12 pages). cited by applicant .
Lovaza.RTM. (omega-3-acid ethyl esters) Capsules, Prescribing
information, GlaxoSmithKline, (Dec. 2010)(12 pages). cited by
applicant .
Lovaza.RTM., Physicians' Desk Reference 2699-2701 (62d ed.,
2008).(4 pages). cited by applicant .
Lovegrove et al., "Moderate fish-oil supplementation reverses
low-platelet, long chain n-3 polyunsaturated fatty acid status and
reduced plasma triacylglycerol concentrations in British
Indo-Asians," Am. J. Clin. Nutr., 79:974-982 (2004). cited by
applicant .
Lu, G., et al., "Omega-3 fatty acids alter lipoprotein subfraction
distributions and the in vitro conversion of very low density
lipoproteins to lowdensity lipoproteins." J Nutr Biochem.,
10:151-158 (1999). cited by applicant .
Lucas, M., et al., "Ethyl-eicosapentaenoic acid for the treatment
of psychological distress and depressive symptoms in middle-aged
women: a double-blind, placebo-controlled, randomized clinical
trial." Am J Clin Nutr 89:641-51 (2009). cited by applicant .
Luria, MH, "Effect of low-dose niacin on high-density lipoprotein
cholesterol and total cholesterol/high density lipoprotein
cholesterol ratio", Arch. Int. Med., 148:2493-2495, (1998). cited
by applicant .
Lvovich V, Scheeline A. Amperometric sensors for simultaneous
superoxide and hydrogen peroxide detection. Anal. Chern.
1997;69:454-462. cited by applicant .
Madhavi et al., "Effect of n-6 and n-3 fatty acids on the survival
of vincristine sensitive and resistant human cervical carcinoma
cells in vitro", Cancer Letters, vol. 84. No. 1, pp. 31-41 (1994).
cited by applicant .
Madsen, L., et al., "Eicosapentaenoic and Docosahexaenoic Acid
Affect Mitochondrial and Peroxisomal Fatty Acid Oxidation in
Relation to Substrate Preference." Lipids 34:951-963 (1999). cited
by applicant .
Mak IT, Weglicki WB. Antioxidant properties of calcium channel
blocking drugs. Methods Enzymol. 1994;234:620-630. cited by
applicant .
Maki et al., "Effects of Adding Prescription Omega-3 Acid Ethyl
Esters to Simvastatin (20 mg/day) on Lipids and Lipoprotein
Particles in Men and Women with Mixed Dyslipidemia," Am. J.
Cardiol., 102:429-433 (Aug. 15, 2008)(Epub May 22, 2008). cited by
applicant .
Maki, K.C., et al., "Baseline lipoprotein lipids and low-density
lipoprotein cholesterol response to prescription omega-3 acid ethyl
ester added to simvastatin therapy." Am J Cardiol., 105:1409-1412
(2010). cited by applicant .
Maki, PhD, et al., "Lipid Responses to a Dietary Docosahexaenoic
Acid Supplement in Men and Women with Below Average Levels of High
Density Lipoprotein Cholesterol." Journal of the American College
of Nutrition, vol. 24, No. 3, 189-199 (2005). cited by applicant
.
Malinowski et al., "Elevation of Low-Density Lipoprotein
Cholesterol Concentration with Over-the-Counter Fish Oil
Supplementation." Annals of Pharmacotherapy 41:1296-1300 (Jul./Aug.
2007). cited by applicant .
Malinski T, Taha Z. Nitric oxide release from a single cell
measured in situ by a porphyrinic-based microsensor. Nature.
1992;358:676-678. cited by applicant .
Mallat, Z., et al., "Apoptosis in the vasculature: mechanisms and
functional importance." British Journal of Pharmacology 130:947-962
(2000). cited by applicant .
Mallet, Z., et al., "Protective role of interleukin-10 in
atherosclerosis." Circ. Res. 85:e17-e24 (1999). cited by applicant
.
Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum
triglyceride and LDL cholesterol and HDL cholesterol concentrations
on coronary heart disease risk in the Helsinki Heart Study.
Implications for treatment. Circulation 85:37-45, 1992. cited by
applicant .
Marangell, Lauren B., M.D., et al., "A Double-Blind,
Placebo-Controlled Stury of the Omega-3 Fatty Acid Docosahexaenoic
Acid in the Treatment of Major Depression", Am. J. Psychiatry,
160(5):996-998, (May 2003). cited by applicant .
Marchioli R, Barzi F, Bomba E, et al, GISSI-Prevenzione
Investigators. Early protection against sudden death by n-3
polyunsaturated fatty acids after myocardial infarction:
time-course analysis of the results of the Gruppo Italiano per lo
Studio della Soprawivenza nell'Infarto Miocardico
(GISSI)-Prevenzione. Circulation. 105(16):1897-1903, 2002. cited by
applicant .
Marckmann, P., "Fishing for heart protection." Am J Clin Nutr,
78:1-2 (2003). cited by applicant .
Marcoux et al., "Plasma remnant-like particle lipid and
apolipoprotein levels in normolipidemic and hyperlipidemic
subjects," Atherosclerosis, vol. 139, pp. 161-171 (Jul. 1998).
cited by applicant .
Marder, "An Approach to Treatment Resistance in Schizophrenia,"
British Journ. Psychiatry, 37:19-22 (1999). cited by applicant
.
Margolis, Simeon "What is Hyperlipidemia?"
(http:www.healthcommunities.com/highcholesterol/whatishyperlipidemia.shtm-
l, accessed Oct. 20, 2015, published Aug. 25, 2011)(4 pages). cited
by applicant .
Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel
method vs the Friedewald equation for estimating low-density
lipoprotein cholesterol levels from the standard lipid profile.
JAMA. 2013;310:2061-8. cited by applicant .
Martinez-Gonzalez J, Raposo B, Rodriguez C, Badimon L.
3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition prevents
endothelial no synthase downregulation by atherogenic levels of
native ldls: Balance between transcriptional and
posttranscriptional regulation. Arterioscler. Thromb. Vasc. Biol.
2001;21:804-809. cited by applicant .
Martinez-Gonzalez, Jose et al., "Estatinas y acidos grasos omega-3.
Disminucion de la mortalidad cardiovascular dependiente e
independiente de la reduccion de la colesterolemia," (2006) Rev Esp
Cardiol Suppl., 6(D):20D-30D [with English abstract]. cited by
applicant .
Martin-Jadraque, R. et al., Effectiveness of low dose crystalline
nicotinic acid in men with low density lipoprotein cholesterol
levels. Arch. Int. Med. 156: 1081-1088. (1996). cited by applicant
.
Martz, "Moving Upstream in Huntington's," Science-Business
eXchange, 2 pgs., 2008. cited by applicant .
Mason et al., "Comparative lipid antioxidant effects of omega-3
fatty acids in combination with HMG-CoA reductase inhibitors,"
Journ. Clin. Lipidology (2011) 5(3):20. cited by applicant .
Mason et al., "Direct evidence for cholesterol crystalline domains
in biological membranes: role in human pathobiology," Biochimica et
Biophysica Acta 198-207 (Mar. 10, 2003). cited by applicant .
Mason et al., "Eicosapentaenoic Acid (EPA) inhibits the formation
of membrane cholesterol crystalline domains by a potent antioxidant
mechanism," Journ. Clin. Lipid., 7(3): 272-273 (2013) [Abstract
only]. cited by applicant .
Mason et al., "Eicosapentaenoic acid inhibits glucose-induced
membrane cholesterol crystalline domain formation through a potent
antioxidant mechanism," Biochim. Biophy. Acta., 1848(2):502-9,
(Feb. 2015). cited by applicant .
Mason et al., "Eicosapentaenoic Acid Inhibits Oxidation of
ApoB-containing Lipoprotein Particles of Different Size In Vitro
When Administered Alone or in Combination With Atorvastatin Active
Metabolite Compared With Other Triglyceride-lowering Agents," J.
Cardiovasc. Pharmacol., 68(1):33-40 (Jul. 2016). cited by applicant
.
Mason et al., "Eicosapentaenoic acid reduces membrane fluidity,
inhibits cholesterol domain formation, and normalizes bilayer width
in atherosclerotic-like model membranes," Biochim. Biophy. Acta.,
1858(12):3131-3140 (Dec. 2016). cited by applicant .
Mason RP, Gonye GE, Chester DW, Herbette LG. Partitioning and
location of Bay K 8644, 1,4-dihydropyridine calcium channel
agonist, in model and biological membranes. Biophys. J.
1989;55(4):769-778. cited by applicant .
Mason RP, Jacob RF, Kubant R, Walter MF, Bellamine A, Jacoby A,
Mizuno Y, Malinski T. Effect of enhanced glycemic control with
saxagliptin on endothelial nitric oxide release and CD40 levels in
obese rats. J. Atheroscler. Thromb. 2011;18:774-783. cited by
applicant .
Mason RP, Jacob RF. Membrane microdomains and vascular biology:
Emerging role in atherogenesis. Circulation. May 6, 2003;
107:2270-2273. cited by applicant .
Mason RP, Kalinowski L, Jacob RF, Jacoby AM, Malinski T. Nebivolol
reduces nitroxidative stress and restores nitric oxide
bioavailability in endothelium of black americans. Circulation.
2005;112:3795-3801. cited by applicant .
Mason RP, Kubant R, Heeba G, Jacob RF, Day CA, Medlin YS, Funovics
P, Malinski T. Synergistic effect of amlodipine and atorvastatin in
reversing ldl-induced endothelial dysfunction. Pharm. Res.
2008;25:1798-1806. cited by applicant .
Mason RP, Walter MF, Day CA, Jacob RF. Active metabolite of
atorvastatin inhibits membrane cholesterol domain formation by an
antioxidant mechanism. J. Biol. Chem. 2006;281(14):9337-9345. cited
by applicant .
Mason RP, Walter MF, Day CA, Jacob RF. Intermolecular differences
for HMG-CoA reductase inhibitors contribute to distinct
pharmacologic and pleiotropic actions. Am. J Cardiol.
2005;96(5A):11F-23F. cited by applicant .
Mason RP, Walter MF, Jacob RF. Effects of hmg-coa reductase
inhibitors on endothelial function: Role of microdomains and
oxidative stress. Circulation. 2004;109:II34-II41. cited by
applicant .
Mason RP, Walter MF, Mason PE. Effect of oxidative stress on
membrane structure: Small angle x-ray diffraction analysis. Free
Radic. Biol. Med. 1997;23(3):419-425. cited by applicant .
Mason RP. Molecular basis of differences among statins and a
comparison with antioxidant vitamins. Am. J. Cardiol.
2006;98:34P-41P. cited by applicant .
Mataki et al., "Effect of Eicosapentaenoic Acid in Combination with
HMG-CoA Reductase Inhibitor on Ligid Metabolism," Int. Med. J.
50(1):35-36 (Mar. 1998). cited by applicant .
Mater, M.K. et al., "Arachidonic acid inhibits lipogenic gene
expression in 3T3-L1 adipocytes through a prostanoid pathway." J.
Lipid Res. 39:1327-1334 (1998). cited by applicant .
Matsumoto, M., et al., "Orally administered eicosapentaenoic acid
reduces and stabilizes atherosclerotic lesions in ApoE-deficient
mice." Atherosclerosis, 197(2):524-533 (2008). cited by applicant
.
Matsuzaki et al., "Incremental Effects of Eicosapentaenoic Acid on
Cardiovascular Events in Statin-Treated Patients with Coronary
Artery Disease," Circ. J. 73:1283-1290 (2009). cited by applicant
.
Matsuzawa, Y., et al., "Effect of Long-Term Administration of Ethyl
Icosapentate (MND-21) in Hyperlipaemic Patients," J. Clin
Therapeutic & Medicines, 7: 1801-16 (1991). cited by applicant
.
Mattson MP. Modification of ion homeostasis by lipid peroxidation:
roles in neuronal degeneration and adaptive plasticity. Trends
Neurosci. 1998;21(2):53-57. cited by applicant .
Mayatepek, E., et al., The Lancet, vol. 352, Leukotriene
C4-synthesis deficiency: a new inborn error of metabolism linked to
a fatal developmental syndrome, pp. 1514-1517 (1998). cited by
applicant .
Mayo Clinic at
http://www.mayoclinic.org.diseases-conditions/high-blood-cholesterol/in-d-
epth/cholesterol (2014)(5 pages). cited by applicant .
Mayo Clinic, Diabetes Diagnosis and Treatment, 1998,
http://www.mayoclinic.org/diseases-conditions/diabetes/diagnosis-treatmen-
t/drc-20371451 (1998-2018). cited by applicant .
McElroy, S.L., et al., "Clozapine in the Treatment of Psychotic
Mood Disorders, Schizoaffective Disorder, and Schizophrenia",
Journal of Clinical Psychiatry, vol. 52, No. 10, pp. 411-414
(1991). cited by applicant .
McIntyre M, Hamilton CA, Rees DD, Reid JL, Dominiczak AF. Sex
differences in the abundance of endothelial nitric oxide in a model
of genetic hypertension. Hypertension. 1997;30:1517-1524. cited by
applicant .
McKenney et al., "Prescription omega-3 fatty acids for the
treatment of hypertriglyceridemia," Am. J. Health Syst. Pharm.,
64(6):595-605 (2007). cited by applicant .
McKenney et al., CMRO, "Comparison of the efficacy of rosuvastatin
versus atorvastatin, simvastatin and pravastatin in achieving lipid
goals: results from the STELLAR trial", 689-98 (2003). cited by
applicant .
McKenney, J., "Niacin for dyslipidemia: considerations in product
selection", Am. J. Health Syst. Pharm., 60:995-1005, (2003). cited
by applicant .
McKenney, J.M. et al. Study ofthe pharmacokinetic interaction
between simvastatin and Erescrigtion omega-3-acid ethyl esters. J.
Clin. Pharmacol. 46, 785-791 (2006). cited by applicant .
McKenney, James et al., "Role of prescription omega-3 fatty acids
in the treatment of Hypertriglyceridemia," Pharmacotherapy,
LNKD--Pubmed: 17461707, vol. 27, No. 5, pp. 715-728 (2007). cited
by applicant .
McKeone et al., "Alterations in serum phosphatidylcholine fatty
acyl species by eicosapentaenoic and docosahexaenoic ethyl esters
in patients with severe hypertriglyceridemia." J. Lipid Res.
38:429-436 (1997). cited by applicant .
McMurchie, E.J., et al., "Incorporation and effects of dietary
eicosapentaenoate (20 : 5(n-3)) on plasma and erythrocyte lipids of
the marmoset following dietary supplementation with differing
levels of linoleic acid." Biochimica et Biophysics Acta,
1045:164-173 (1990). cited by applicant .
McNamara JR, et al., Remnant-like particle (RLP) Cholesterol is an
independent cardiovascular disease risk factor in women: results
from the Framingham Heart Study, Atherosclerosis, vol. 154(1), pp.
229-36 (2001). cited by applicant .
MedlinePlus. "Coronary heart disease," Available at:
https://medlineplus.gov/ency/article/007115.htm (review date Jul.
14, 2015)(accessed Sep. 2, 2016)(5 pages). cited by applicant .
Menuet, R. et al., "Importance and management of dyslipidemia in
the metabolic syndrome," American Journal of the Medical Sciences
200512 US, vol. 33, No. 6, pp. 295-302 (2005). cited by applicant
.
Merched, A.J., et al., "Atherosclerosis: evidence for impairment of
resolution of vascular inflammation governed by specific lipid
mediators." FASEB J. 22:3595-3606 (2008). cited by applicant .
Merkl et al., "Antisense Oligonucleotide Directed to Human
Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized
Phospholipids on Human Apolipoprotein B-100 Particles in
Lipoprotein(a) Transgenic Mice," Circulation, vol. 118, pp. 743-753
(2008). cited by applicant .
Mesa, M., "Effects of oils rich in Eicosapentaenoic and
docosahexaenoic acids on the oxidizability and thrombogenicity of
low-density lipoprotein," Artherosclerosis 175, pp. 333-343 (2004).
cited by applicant .
Metcalf, R.G. et al., "Effect of dietary n-3 polyunsaturated fatty
acids on the inducibility of ventricular tachycardia in patients
with ischemic cardiomyopathy." Am J Cardiol 101:758-761 (2008).
cited by applicant .
Metcalf, R.G., et al., "Effects of fish-oil supplementation on
myocardial fatty acids in humans." Am J Clin Nutr 85:1222-28
(2007). cited by applicant .
Meyer, et al., "Dose-Dependent Effects of Docosahexaenoic Acid
Supplementation on Blood Ligids in Statin-Treated Hygerligidaemic
Subjects." Ligids, 42:109-115 (2007). cited by applicant .
Meyers, et al., "Nicotinic acid induces secretion of prostaglandin
D2 in human macrophages: An in vitro model of the niacin-flush",
Atherosclerosis, 192:253-258, (2007). cited by applicant .
Micheletta F, Natoli S, Misuraca M, Sbarigia E, Diczfalusy U,
Iuliano L. Vitamin E supplementation in patients with carotid
atherosclerosis: Reversal of altered oxidative stress in plasma but
not in plaque. Arterioscler. Thromb. Vasc. Biol. 2004;24:136-140.
cited by applicant .
Michos et al., "Niacin and Statin Combination Therapy for
Atherosclerosis Regression and Prevention of Cardiovascular Disease
Events," Journ. Amer. Coll. Cardiol., vol. 59, No. 23:2058-2064
(2012). cited by applicant .
Mii S. et al., "Perioperative use of eicosapentaenoic acid and
patency of infrainguinal vein bypass: a retrospective chart
review." Curr Ther Res Clin Exp. 68:161-174 (2007). cited by
applicant .
Miles, et al., "Effect of orlistat in overweight and obese patients
with type 2 diabetes treated with metformin," Diabetes Care,
25(7):1123-1128 (2002). cited by applicant .
Miller AK, DiCicco RA, Freed MI. The effect of ranitidine on the
pharmacokinetics of rosiglitazonein healthy adult male volunteers.
Clin. Ther. 2002;24:1062-1071. cited by applicant .
Miller AK, Inglis AM, Culkin KT, Jorkasky DK, Freed MI. The effect
of acarbose on the pharmacokinetics of rosiglitazone. Eur. J. Clin.
Pharmacol. 2001;57:105-109. cited by applicant .
Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride
levels beyond low-density lipoprotein cholesterol after acute
coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol
51:724-730, 2008. cited by applicant .
Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and
cardiovascular disease: a scientific statement from the American
Heart Association. Circulation. 2011;123:2292-2333. cited by
applicant .
Miller M. Current perspectives on the management of
hypertriglyceridemia. Am Heart J 140:232-40, 2000. cited by
applicant .
Miller, M., et al., "Impact of lowering triglycerides on raising
HDL-C in hypertriglyceridemic and non-hypertriglyceridemic
subjects." International Journal of Cardiology 119:192-195 (2007).
cited by applicant .
Minihane, A.M., et al., "ApoE polymorphism and fish oil
supplementation in subjects with an atherogenic lipoprotein
phenotype." Arterioscler. Thromb. Vasc. Biol. 20:1990-1997 (2000).
cited by applicant .
Mishra, A., et al., "Oxidized omega-3 fatty acids inhibit
NF-.kappa.B activation via a PPAR.alpha.-Dependent Pathway."
Arterioscler Thromb Vasc Biol. 24:1621-1627 (2004). cited by
applicant .
Missouri DUReport, Statin Therapy (Oct./Nov. 2003) Drug Use Review
Newsletter 8(6):1-9. cited by applicant .
Mita, T. T et al., Eicosapentaenoic acid reduces the progression of
carotid intima-media thickness in patients with type 2 diabetes,
Atherosclerosis 191:162-167 (2007). cited by applicant .
Mizota M, Katsuki Y, Mizuguchi K, Endo S, Miyata H, Kojima M,
Kanehiro H et al. "Pharmacological studies of eicosapentaenoic acid
ethylester (EPA E) on high cholesterol diet-fed rabbits," Nippon
Yakurigaku Zasshi, 91:255-66 (1988) (with English abstract). cited
by applicant .
Mizota M, Katsuki Y, Mizuguchi K, Endo S, Miyata H, Kojima M,
Kanehiro H et al. "The effects of eicosapentaenoic acid ethylester
(EPA E) on arterial thrombosis in rabbits and vascular lesions in
rats," Nippon Yakurigaku Zasshi, 91:81-9 (1988)(with English
abstract). cited by applicant .
Mizuguchi K, Yano T, Kojima M, Tanaka Y, Ishibashi M, Masada A,
Sato M et al. "Hypolipidemic effect of ethyl
all-cis-5,8,11,14,17-eicosapentaenoate (EPA-E) in rats," Jpn J
Pharmacol., 59:3307-12 (1992). cited by applicant .
Mizuguchi, K., et al., "Ethyl all-cis-5,8,11,14,17-icosapentaenoate
modifies the biochemical properties of rat very low-density
lipoprotein." European Journal of Pharmacology, 231:221-227 (1993).
cited by applicant .
Mizuguchi, K., et al., "Mechanism of the lipid-lowering effect of
ethyl all-cis-5,8,11,14,17-icosapentaenoate." European Journal of
Pharmacology, 231:121-127 (1993). cited by applicant .
Mochida Press Release, Pharmaceutical Col., Ltd.: Conclusion of
Distributorship Agreement Concerning Switch-OTC Drug for
Hyperlipidemia Treatment, Epadel, (2009)(1 page). cited by
applicant .
Mochida, Announcement, "Mochida Announces Completion of "JELIS"
Major Clinical Trial for Epadel," Mar. 22, 2005 (2 pages). cited by
applicant .
Mochida's Epadel Reduces Risk of Stroke Recurrence--New Results of
JELIS Major Clinical Trial, JCNNetwork Newswire Nov. 13, 2006 (2
pages). cited by applicant .
Mora, S., et al., "LDL particle subclasses, LDL particle size, and
carotid atherosclerosis in the Multi-Ethnic Study of
Atherosclerosis (MESA)." Atherosclerosis. 2007;192:211-217 (2007).
cited by applicant .
Mori et al., "Differential Effects of Eicosapentaenoic Acid and
Docosahexaenoic Acid on Vascular Reactivity of the Forearm
Microcirculation in Hyperlipidemic, Overweight Men," Circulation,
102:1264-1269 (2000). cited by applicant .
Mori TA, Woodman RJ. "The independent effects of eicosapentaenoic
acid and docosahexaenoic acid on cardiovascular risk factors in
humans," Curr Opin Clin Nutr Metab Care 2006; 9:95-104 (2006).
cited by applicant .
Mori TA. Omega-3 fatty acids and blood pressure. Cell Mol Biol.;
Feb. 25, 2010;56(1):83-92. cited by applicant .
Mori, et al., "Purified Eicosapentaenoic and docosahexaenoic acids
have differential effects on serum lipids and lipoproteins, LDL
particle size, glucose, and insulin in mildly hyperlipidemic men,"
Am J Clin Nutr 71:1085-1094 (2000). cited by applicant .
Mori, T. et al., Effect of Eicosapentaenoic acid and
docosahexaenoic acid on oxidative stress and inflammatory markers
in treated-hypertensive type 2 diabetic subjects, Free Radical
Biology & Medicine, vol. 35, No. 7, pp. 772-781 (2003). cited
by applicant .
Mori, Trevor A., et al., "Docosahexaenoic Acid but Not
Eicosapentaenoic Acid Lowers Ambulatory Blood Pressure and Heart
Rate in Humans", Hypertension, 34(2):253-60 (Aug. 1999). cited by
applicant .
Morita, I., et al., "Effects of purified eicosapentaenoic acid on
arachidonic acid metabolism in cultured murine aortic smooth muscle
cells, vessel walls and platelets." Lipids 18:42-490 (1983). cited
by applicant .
Morris M, Sacks F, Rosner B. Does fish oil lower blood pressure? A
meta-analysis of controlled trials. Circ. 1993;88:523-533. cited by
applicant .
Morrow, JD, "Release of markedly increased quantities of
prostaglandin D2 in vivo in humans following the administration of
nicotinic acid", Prostaglandins, 38:263-274, (1989). cited by
applicant .
Morton, R.E., "Specificity of lipid transfer protein for molecular
species of cholesteryl ester." J Lipid Res., 27:523-529 (1986).
cited by applicant .
Mosher LR et al., "Nicotinic Acid Side Effects and Toxicity: A
review," Am J Psychiat., 126: 1290-1296 (1970). cited by applicant
.
Mostad et al., "Effects of Marine N-3 Fatty Acid Supplementation on
Lipoprotein Subclasses Measured by Nuclear Magnetic Resonance in
Subjects with Type II Diabetes," European Journ. Clin. Nutr.,
62(3):419-429 (2007). cited by applicant .
Mostad, I.L, et al., "Effects of n-3 fatty acids in subjects with
type 2 diabetes: reduction of insulin sensitivity and
time-dependent alteration from carbohydrate to fat oxidation." Am J
Clin Nutr 84:540-50 (2006). cited by applicant .
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al; on
behalf of the American Heart Association Statistics Committee and
Stroke Statistics Subcommittee. Heart disease and stroke
statistics--2016 update: a report from the American Heart
Association [published online ahead of print Dec. 16, 2015].
Circulation. doi: 10.1161/CIR.0000000000000350. cited by applicant
.
Mozaffarian D, Geelen A, Brouwer I, Geleijnse J, Zock P, Katan M.
Effect of Fish Oil on Heart Rate in Humans A Meta-Analysis of
Randomized Controlled Trials. Circ.2005; 112:1945-1952. cited by
applicant .
Mozaffarian D, Marchioli R, Macchia A, et al. Fish Oil and
Postoperative Atrial Fibrillation The Omega-3 Fatty Acids for
Prevention of Post-operative Atrial Fibrillation (OPERA) Randomized
Trial. JAMA. Nov. 21, 2012;308(19):2001-11. cited by applicant
.
Mozaffarian D, Psaty B, Rimm E, Lemaitre R, Burke G, Lyles M,
Lefkowitz D, Siscovick D. Fish Intake and Risk of Incident Atrial
Fibrillation. Circ.2004; 110:368-373. cited by applicant .
Mozaffarian et al., "Omega-3 fatty acids and cardiovascular
disease: effects on risk factors, molecular pathways and clinical
events," J. Am. Coll. Cardiol. (2011) 58(2):2047-2067. cited by
applicant .
Mozaffarian, "JELIS, fish oil, and cardiac events,"
www.thelancet.com vol. 369, pp. 1062-1063 (2007). cited by
applicant .
Mozaffarian, D., "Fish and n-3 fatty acids for the prevention of
fatal coronary heart disease and sudden cardiac death." Am J Clin
Nutr, 87:1991S-6S (2008). cited by applicant .
Mozaffarian, D., et al., "Dietary fish and .omega.-3 fatty acid
consumption and heart rate variability in US adults." Circulation,
117:1130-1137 (2008). cited by applicant .
Murck et al., "Ethyl-EPA in Huntington disease--Potentially
relevant mechanism of action," Brain Research Bulletin, 72:159-164
(2007) (available online Nov. 15, 2006). cited by applicant .
Murphy SA, Cannon CP, Blazing MA, et al. Reduction in total
cardiovascular events with ezetimibe/simvastatin post-acute
coronary syndrome. J Am Coll Cardiol. 67(4):353-361 (publication
date Feb. 2, 2016; epublication date Jan. 25, 2016). cited by
applicant .
Naba, H., et al., "Improving effect of ethyl eicosapentanoate on
statin-induced rhabdomyolysis in Eisai hyperbilirubinemic rats."
Biochemical and Biophysical Research Communications, 340:215-220
(2006). cited by applicant .
Nagakawa et al., Effect of [EPA] on the Platelet Aggregation and
Composition of Fatty Acid in Man: A Double Blind Study,
Atherosclerosis 47(1):71-75 (1983). cited by applicant .
Naik H, Wu JT, Palmer R, McLean L. The effects of febuxostat on the
pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate.
Br. J. Clin. Pharmacol. Jan. 13, 2012;74:327-335. cited by
applicant .
Nakamura et al., Remnant lipoproteniemia is a risk factor for
endothelial vasomotor dysfuction and coronary artery disease in
metabolic syndrome, Atherosclerosis, vol. 181 (2), pp. 321-327
(2005). cited by applicant .
Nakamura, et al., "Effects of Eicosapentaenoic Acids on
Remnant-like Particles, Cholesterol Concentrations and Plasma Fatty
Acid Composition in Patients with Diabetes Mellitus." in vivo 12:
311-314 (1998). cited by applicant .
Nakamura, H., et al., "Evaluation of ethyl icosapentate in the
treatment of hypercholesterolemia in kidney transplant recipients."
Transplantation Proceedings, 30:3047-3048 (1998). cited by
applicant .
Nakamura, N. et al., "Joint effects of HMG-CoA reductase inhibitors
and eicosapentaenoic acids on serum lipid profile and plasma fatty
acid concentrations in patients with hyperlipidemia," International
Journal of Clinical and Laboratory Research, Springer, Berlin, DE
LNKD-DOI: 10.1007/S005990050057, vol. 29, No. 1, pp. 22-25 (1999).
cited by applicant .
Nambi V, Bhatt DL. Primary prevention of atherosclerosis: Time to
take a selfie? J Am Coll Cardiol 2017;70(24):2992-4 (publication
date Dec. 19, 2017; epublication date Dec. 11, 2017). cited by
applicant .
Nambi, V. et al "Combination therapy with statins and omega-3 fatty
acids." Am J Cardiol 98:34i-38i(2006). cited by applicant .
Nasa, et al., "Long-Term Supplementation With Eicosapentaenoic Acid
Salvages Cardiomyocytes From Hypoxia/Reoxygenation-Induced Injury
in Rats Fed With Fish-Oil-Deprived Diet," Jpn. J. Pharmacol. 77,
137-146 (1998). cited by applicant .
National Kidney Foundation, "Glomerular Filtration Rate (GFR),"
Jan. 30, 2017 (Jan. 30, 2017), retrieved on Jul. 30, 2018 from
https://web/archive.org/web/20170130183218/https://www.kidney.org/atoz/co-
ntent/gfr; entire document, especially p. 1 paragraph 1 and p. 3,
paragraph 2. cited by applicant .
National Kidney Foundation, "The Heart and Kidney Connection," Apr.
17, 2017 (Apr. 17, 2017), retrieved on Jul. 30, 2018 from
https://web.archive.org/web/2017041700416/https://www.kidney.org/atoz/con-
tent/heart-and-kidney-connection; entire document, especially p. 2,
paragraph 1. cited by applicant .
Natsuno et al., "Clinical Effects of Eicosapentaenoic Acid on
Type-2 Diabetes Effects on Serum Lipids, Pulse Wave Speed, and
Ankle-Brachial Blood Pressure Index," Diagnosis and Treatment
93(12):133-137 (2005)(16 pages). cited by applicant .
Nattel, S. et al., "Atrial remodeling and atrial fibrillation:
Mechanisms and implications." Circ Arrhythmia Electrophysiol,
1:62-73 (2008). cited by applicant .
Needleman P, Raz A, Minkes MS, Ferrendelli JA, Sprecher H. Triene
prostaglandins: prostacyclin and thromboxane biosynthesis and
unique biological properties. Proc Natl Acad Sci USA.
1979;76:944-948. cited by applicant .
Negre-Salvayre, A., et al., "Advanced lipid peroxidation end
products in oxidative damage to proteins. Potential role in
diseases and therapeutic prospects for the inhibitors." British
Journal of Pharmacology 153:6-20 (2008). cited by applicant .
Nelson JR, Wani O, May HT, Budoff M. Potential benefits of
eicosapentaenoic acid on atherosclerotic plaques. Vascul Pharmacol.
91:1-9 (publication date Apr. 2017; epublication date Mar. 2,
2017). cited by applicant .
Nelson, G.J., et al., "The Effect of Dietary Docosahexaenoic Acid
on Plasma Lipoproteins and Tissue Fatty Acid Composition in
Humans", Lipids, 32(11):1137-1146, (1997). cited by applicant .
Nemets, Boris, M.D., "Addition of Omega-3 Fatty Acid to Maintenance
Medication Treatment for Recurrent Unipolar Depressive Disorder",
Am. J. Psychiatry, 159(3):477-479, (Mar. 2002). cited by applicant
.
Nemoto et al., "Ethyl-eicosapentaenoic Acid Reduces Liver Lipids
and Lowers Plasma Levels of Lipids in Mice Fed a High-Fat Diet, in
vivo," 23:685-690 2009). cited by applicant .
Nenseter, MS et al., "Effect of dietary supplementation with n-3
polyunsaturated fatty acids on physical properties and metabolism
of low density lipoprotein in humans," Arterioscler. Thromb. Vasc.
Biol., 12;369-379 (1992). cited by applicant .
Nestel, et al., "The n-3 fatty acids eicosapentaenoic acid and
docosahexaenoic acid increase systemic arterial compliance in
humans," Am J Clin Nutr., 76:326-30 (2002). cited by applicant
.
Nestel, P.J., "Effects of N-3 fatty acids on lipid metabolism." Ann
Rev Nutr., 10:149-167 (1990). cited by applicant .
Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased
cardiovascular risk in hypertriglyceridemic patients with
statin-controlled LDL cholesterol. J Clin Endocrinol Metab
103(8):3019-27 (publication date Aug. 1, 2018; epublication date
May 29, 2018). cited by applicant .
Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased
residual cardiovascular risk in patients with diabetes and high vs.
normal triglycerides despite statin-controlled LDL Cholesterol.
Diabetes Obes Metab (publication date Sep. 17, 2018; epublication
date Sep. 17, 2018). cited by applicant .
Niemi M, Backman JT, Grantors M, Laitila J, Neuvonen M, Neuvonen
PJ. Gemfibrozil considerably increases the plasma concentrations of
rosiglitazone. Diabetologia. 2003;46: 1319-1323. cited by applicant
.
Niemi M, Backman JT, Neuvonen PJ. Effects oftrimethoprim and
rifampin on the pharmacokinetics of the cytochrome P450 2C8
substrate rosiglitazone. Clin. Pharmacol. Ther. 2004;76:239-249.
cited by applicant .
Nigon F, Lesnik P, Rouis M, Chapman MJ. Discrete subspecies of
human low density lipoproteins are heterogeneous in their
interaction with the cellular LDL receptor. J. Lipid Res.
1991;32(11):1741-1753. cited by applicant .
Nippon Rinsho, Metabolic Syndrome 2nd Edition--Basics and New
Clinical Findings, Jan. 20, 2011, Special Issue 1 (vol. 992), pp.
503-506 (with English translation). cited by applicant .
Nishikawa M. et al., "Effects of Eicosapentaenoic acid (EPA) on
prostacyclin production in diabetics. GC/MS analysis of PG12 and
PG13 levels" Methods Find Exp Clin Pharmacol. 19(6):429-33 (1997).
cited by applicant .
Nobukata, H., et al., "Age-related changes in coagulation,
fibrinolysis, and platelet aggregation in male WBN/Kob rats."
Thrombosis Research 98: 507-516 (2000). cited by applicant .
Nobukata, H., et al., "Long-term administration of highly purified
eicosapentaenoic acid ethyl ester improves the dysfunction of
vascular endothelial and smooth muscle cells in male WBN/Kob rats."
Metabolism, 49(12): 1588-1591 (2000). cited by applicant .
Nobukata, H., et al., "Long-term administration of highly purified
eicosapentaenoic acid ethyl ester prevents diabetes and
abnormalities of blood coagulation in male WBN/Kob rats."
Metabolism, 49(12): 912-919 (2000). cited by applicant .
Noguchi et al., "Chemoprevention of DMBA-induced mammary
carcinogenesis in rats by low-dose EPA and DHA." Br. J. Cancer
75(3): 348-353 (1997). cited by applicant .
Nomura et al., "The effects of pitavastatin, eicosapentaenoic acid
and combined therapy on platelet-derived microparticles and
adiponectin in hyperlipidemic, diabetic patients." Platelets,
20(1):16-22 (2009). cited by applicant .
Nomura S, Shouzu A, Omoto S, et al. Effects of eicosapentaenoic
acid on endothelial cell-derived microparticles, angiopoietins and
adiponectin in patients with type 2 diabetes. J Atheroscler Throm.
2009;16:83-90. cited by applicant .
Nourooz-Zadeh, J., et al., "Urinary 8-epi-PGF2.alpha. and its
endogenous .beta.-oxidation products (2,3-dinor and
2,3-dinor-5,6-dihydro) as biomarkers of total body oxidative
stress." Biochemical and Biophysical Research Communications
330:731-736 (2005). cited by applicant .
Nozaki S. et al., "Effects of purified Eicosapentaenoic acid ethyl
ester on plasma lipoproteins in primary hypercholesterolemia" Int J
Vitam Nutr Res. 62(3):256-260 (1992). cited by applicant .
Obata, et al., "Eicosapentaenoic acid inhibits prostaglandin D2
generation by inhibiting cyclo-oxygenase in cultured human mast
cells", Clin. & Experimental Allergy, 29:1129-1135, (1999).
cited by applicant .
O'Donnell, C.J., et al., "Leukocyte telomere length and carotid
artery intimal medial thickness--the Framingham heart study."
Arteriosclerosis, Thrombosis, and Vascular Biology.28:1165-1171
(2008). cited by applicant .
Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Luscher
TF. Reduced endothelial nitric oxide synthase expression and
production in human atherosclerosis. Circulation.
1998;97:2494-2498. cited by applicant .
Oh, Robert C et al., Management of Hypertriglyceridemia, American
Family Physician, LNKD-PUBMED: 17508532, vol. 75, No. 9, pp.
1365-1371 (2007). cited by applicant .
Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases
endothelial superoxide anion production. J. Clin. Invest.
1993;91:2546-2551. cited by applicant .
Ohashi, Journal of Clinical and Experimental Medicine, Feb. 14,
2009, vol. 228, No. 7, pp. 795-805 (with English translation).
cited by applicant .
Okuda, Y. et al., Eicosapentaenoic acid enhances nitric oxide
production by cultured human endothelial cells. Biochem. Biophys.
Res. Commun. 232: 487-491 (1997). cited by applicant .
Okuda, Y., et al., "Long-term effects of eicosapentaenoic acid on
diabetic peripheral neuropathy and serum lipids in patients with
type II diabetes mellitus." Journal of Diabetes and Its
Complications 10:280-287 (1996). cited by applicant .
Okumura, T., et al., "Eicosapentaenoic acid improves endothelial
function in hypertriglyceridemic subjects despite increased lipid
oxidizability." Am J Med Sci 324(5):247-253 (2002). cited by
applicant .
Oliw, E.H., et al., "Biosynthesis of prostaglandins from
17(18)epoxy-eicosatetraenoic acid, a cytochrome P-450 metabolite of
eicosapentaenoic acid." Biochimica el Biophysica Acta, 1126,
261-268 (1992). cited by applicant .
Olofsson et al., "Apolipoprotein B: a clinically important
apolipoprotein which assembles atherogenic lipoproteins and
promotes the development of atherosclerosis" Journal of Internal
Medicine, 258: 395-410 (2005). cited by applicant .
Omacor Summary of Product Characteristics, Pronova BioPharma Norge
AS. Lysaker, Norway, Mar. 2015. cited by applicant .
Omacor.RTM. Prescribing Information (Omega-3-acid ethyl esters,
capsules) (2004). (9 pages). cited by applicant .
Omacor.RTM., Physicians' Desk Reference 2735 (60th ed. 2006)(3
pages). cited by applicant .
Ona, V.O., et al., Nature, vol. 399, Inhibition of caspase-1 slows
disease progression in a mouse model of Huntington's disease, pp.
263-267 (1999). cited by applicant .
Ooi EM, "Apolipoprotein C-III: Understanding an emerging
cardiovascular risk factor", Clin.Sci. (London), vol. 114, pp.
611-624 (2008). cited by applicant .
Opalinska et al., "Increasing Level of Prostate-Specific Antigen
and Prostate Cancer Risk Factors Among 193 Men Examined in
Screening Procedure," Ann. Univ. Curie Sklowoska Med., 58(2):57-63
(Abstract Only)(2003)(2 pages). cited by applicant .
Origin Trial Investigators (The). n-3 fatty acids and
cardiovascular outcomes in patients with dysglycemia. N Engl J Med
2012;367:309-318. cited by applicant .
O'Riordan, "DHA and EPA have differential effects on
LDL-cholsterol," May 24, 2011 [online][Retrieved on Aug. 21, 2015]
Retrieved from website: http://www.medscape.com/viewarticle/743305
(2 pages). cited by applicant .
Osher et al., "Omega-3 Eicosapentaenoic Acid in Bipolar Depression:
Report of a Small Open-Label Study," J. Clin. Psych. 66:726-729
(2005). cited by applicant .
Otvos et al., "Clinical Implications of Discordance Between LDL
Cholesterol and LDL Particle Number," J. Clin. Lipidol,
5(2):105-113 (Mar.-Apr. 2011)(available online Mar. 1, 2011). cited
by applicant .
Ou Z, Ou J, Ackerman AW, Oldham KT, Pritchard KA, Jr. L-4f, an
apolipoprotein a-1 mimetic, restores nitric oxide and superoxide
anion balance in low-density lipoprotein-treated endothelial cells.
Circulation. 2003;107:1520-1524. cited by applicant .
Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N,
Hirata K, Yasui H, Sakurai H, Yoshida Y, Masada M, Yokoyama M.
Overexpression of endothelial nitric oxide synthase accelerates
atherosclerotic lesion formation in apoe-deficient mice. J. Clin.
Invest. 2002; 110:331-340. cited by applicant .
Ozawa, Akio, Nakamura E, Jinbo H. Fujita T, Hirai A, Terano T,
Hamazaki T et al., "Determination of highger fatty acids in various
lipid fractions of human plasma, platelets, and erythrocyte
membrane using thin layer chromatography and gas chromatography,"
Bunseki Kagaku, 32:174-8 (1982) (with English abstract). cited by
applicant .
Padgett et al., "Phylogenetic and immunological definition of four
lipoylated proteins from Novosphingobium aromaticivorans,
implications for primary biliary cirrhosis," Journ. Autoimmunity
24:209-219 (May 2005)(available online Feb. 24, 2005). cited by
applicant .
Park JH, Park DI, Kim HJ, et al. Metabolic syndrome is associated
with erosive esophagitis. World J. Gastroenterol. Sep. 14, 2008
(35): 5442-7. cited by applicant .
Park JY, Kim KA, Kang MH, Kim SL, Shin JG. Effect of rifampin on
the pharmacokinetics of rosiglitazone in healthy subjects. Clin.
Pharmacol. Ther. 2004;75:157-162. cited by applicant .
Park, Y., et al., "Omega-3 fatty acid supplementation accelerates
chylomicron triglyceride clearance." J. Lipid Res. 44:455-463
(2003). cited by applicant .
Pase M, Grima N, Sarris J. Do long-chain n-3 fatty acids reduce
arterial stiffness? A meta-analysis of randomized controlled
trials.Br J Nutr.2011; 106:974-980. cited by applicant .
Patel et al., "Rosiglitazone monotherapy improves glycaemic control
in patients with type 2 diabetes: a twelve-week, randomized,
placebo-controlled study," Diabetes, Obesity and Metabolism, vol.
1, 99. 165-172 (1999). cited by applicant .
Paton, CM, Ntambi, JM., Biochemical and physiological function of
stearoyl-CoA desaturase, Am. J. Physiol. Endocrinol. Metab.
2009;297:E28-E37. cited by applicant .
PCT/GB00/00164 International Search Report dated Oct. 20, 2000 (8
pages). cited by applicant .
PCT/US2011/062247 International Search Report and Written Opinion
dated Jun. 14, 2012 (12 pages). cited by applicant .
PCT/US2013/020526 International Search Report dated Mar. 29, 2013
(2 pages). cited by applicant .
PCT/US2013/048241 International Search Report dated Dec. 13, 2013
(3 pages). cited by applicant .
PCT/US2013/048516 International Search Report dated Dec. 20, 2013
(3 pages). cited by applicant .
PCT/US2013/048559 International Search Report dated Dec. 13, 2013
(3 pages). cited by applicant .
PCT/US2013/068647 International Search Report and Written Opinion
dated May 13, 2014 (18 pages). cited by applicant .
PCT/US2014/019454 International Search Report and Written Opinion
dated Jun. 3, 2014 (12 pages). cited by applicant .
Pedersen RS, Damkier P, Brosen K. The effects of human CYP2C8
genotype and fluvoxamine on the pharmacokinetics of rosiglitazone
in healthy subjects. Br. J. Clin. Pharmacol. 2006;62:682-689. cited
by applicant .
Pedersen, T., et al., "Randomised trial of cholesterol lowering in
4444 patients with coronary heart disease: the Scandinavian
Simvastation Survival Study (4S)", The Lancet, No. 19, vol. 344,
8934, p. 1383-1389 (1994). cited by applicant .
Peet et al., "A Dose-Ranging Study of the Effects of
Ethyl-Eicosapentaenoate in Patients with Ongoing Depression Despite
Apparently Adequate Treatment with Standard Drugs", Arch. Gen.
Psychiatry, 59:913-919, (2002). cited by applicant .
Peet, M., et al., Phospholipid Spectrum Disorder in Psychiatry pp.
1-19, (1999). cited by applicant .
Pejic et al., "Hypertriglyceridimia," Journ. Amer. Board Fam. Med.,
vol. 19(3):310-316 (2006). cited by applicant .
Pennathur S, Heinecke JW. Mechanisms for oxidative stress in
diabetic cardiovascular disease. Antioxid. Redox Signal.
2007;9(7):955-969. cited by applicant .
Piccini, Monica, et al., Genomics, vol. 47, "FACL4, a new gene
encoding long-chain acyl-CoA synthetase 4, is deleted in a family
with Alport syndrome, elliptocytosis, and mental retardation," pp.
350-358 (1998). cited by applicant .
Piche, "Tumor Necrosis Factor-Alpha, and Fibrinogen to Abdominal
Adipose Tissue, Blood Pressure, and Cholesterol and Triglyceride
Levels in Healthy Postmenopausal Women", American Journal of
Cardiology, 2005, 96(1), 92-97. cited by applicant .
Pike, NB, "Flushing out the role of GPR109A (HM74V) in the clinical
efficacy of nicotinic acid", J. Clin. Invest., 115:3400-3403,
(2005). cited by applicant .
Plusepa.RTM. Product brochure "Super Critically Different from
Other Omega-3 Fish Oil Supplements for Depression and ADHD," by
Minami Nutrition (Apr. 2009, pp. 1-6). cited by applicant .
Pollin TI, Damcott CM, Shen H, et al. A null mutation in human
APOC3 confers a favorable plasma lipid profile and apparent
cardioprotection. Science. 2008;322(5908):1702-1705. cited by
applicant .
Pownall, H.J., et al., "Correlation of serum triglyceride and its
reduction by .omega.-3 fatty acids with lipid transfer activity and
the neutral lipid compositions of high-density and low-density
lipoproteins." Atherosclerosis 143:285-297 (1999). cited by
applicant .
Press Release: Amarin Corporation Says Huntington's Diease Drug
Failed in Trials, http://www.fiercebiotech.com/node/6607/print
(Apr. 24, 2007) (Printed on Aug. 22, 2008)(2 pages). cited by
applicant .
Pritchard KA, Ackerman AW, Ou J, Curtis M, Smalley DM, Fontana JT,
Stemerman MB, Sessa WC. Native low-density lipoprotein induces
endothelial nitric oxide synthase dysfunction: Role of heat shock
protein 90 and caveolin-1. Free Radic. Biol. Med. 2002;33:52-62.
cited by applicant .
Pritchard KA, Jr., Groszek L, Smalley DM, Sessa WC, Wu M, Villalon
P, Wolin MS, Stemerman MB. Native low-density lipoprotein increases
endothelial cell nitric oxide synthase generation of superoxide
anion. Circ. Res. 1995;77:510-518. cited by applicant .
Puri et al., "Reduction in Cerebral Atrophy Associated with
Ethyl-eicosapentaenoic Acid Treatment in Patients with Huntington's
Disease," Journ. Int'l. Med. Research, 36:896-905 (Oct. 1, 2008).
cited by applicant .
Puri, B., et al., "Eicosapentaenoic Acid in Treatment-Resistant
Depression Associated with Symptom Remission, Structural Brain
Changes and Reduced Neuronal Phospholipid Turnover," Int J Clinical
Practice, 55:560-563 (2001). cited by applicant .
Puri, B., et al., Archives of General Psychiatry, No. 55,
"Sustained remission of positive and negative symptoms of
schizophrenia following treatment with eicosapentaenoic acid," pp.
188-189, (1998). cited by applicant .
Puri, B.K., et al., "Ethyl-EPA in Huntington Disease: A
Double-Blind, Randomized, Placebo-Controlled Trial", Neurology,
65:286-292, (2005). cited by applicant .
Qi, K., et al., "Omega-3 fatty acid containing diets decrease
plasma triglyceride concentrations in mice by reducing endogenous
triglyceride synthesis and enhancing the blood clearance
oftriglyceride-rich particles." Clinical Nutrition 27(8):424-430
(2008). cited by applicant .
Rader, Lipid Disorders, in Eric J. Topol (ed.)Textbook of
Cardiovascular Medicine pp. 55-75 (2007). cited by applicant .
Rahimy M, Hallen B, Narang P. Effect of tolterodine on the
anticoagulant actions and pharmacokinetics of single-dose warfarin
in healthy volunteers. Arzneimittelforschung 2002 52 (12): 890-5.
cited by applicant .
Raitt, M.H., et al., "Fish oil supplementation and risk of
ventricular tachycardia and ventricular fibrillation in patients
with implantable defibrillators--a randomized controlled trial."
JAMA. 293(23):2884-2891 (2005). cited by applicant .
Rambjor, Gro S., et al., "Elcosapentaenoic Acid is Primarily
Responsible for Hypotrigylceridemic Effect of Fish Oil in Humans",
Fatty Acids and Lipids from Cell Biology to Human Disease:
Proceedings of the 2nd international Congress of the ISSFAL
(International Society for the Study of Fatty Acids and Lipids,
AOCS Press, 31:S-45-S-49, (1996). cited by applicant .
Randomised trial of cholesterol lowering in 4444 patients with
coronary heart disease. The Scandinavian Simvastatin Survival
Study, Lancet. 344: 1383-1389 (1994). cited by applicant .
Rao MN, Mullangi R, Katneni K, et al. Lack of effect of sucralfate
on the absorption and pharmacokinetics of rosiglitazone. J. Clin.
Pharmacol. 2002;42:670-675. cited by applicant .
Rauch B, Rudolf R, Schneider S, et al. OMEGA, a randomized,
placebo-controlled trial to test the effect of highly purified
omega-3 fatty acids on top of modern guideline-adjusted therapy
after myocardial infarction. Circulation. 2010;122:2152-2159. cited
by applicant .
Rees DD, Palmer RM, Moncada S. The role of endothelium-derived
nitric oxide in the regulation of blood pressure. Proc. Natl. Acad.
Sci. USA. 1989;86:3375-3378. cited by applicant .
Reich, "Formulation and physical properties of soft capsules,"
Pharmaceutical capsules. (2004) Chapter 11:201-212. cited by
applicant .
Reiffel, J.A., et al., "Antiarrhythmic effects of omega-3 fatty
acids." Am J Cardiol 98:50i- 60i (2006). cited by applicant .
Reiner Z, Catapano AL, De BG, et al. ESC/EAS Guidelines for the
management of dyslipidaemias: the Task Force for the management of
dyslipidaemias of the European Society of Cardiology (ESC) and the
European Atherosclerosis Society (EAS). Eur. Heart J.
2011;32:1769-1818. cited by applicant .
Richter, Werner O. , "Hypertriglyceridamie: Ein klinischer
Leitfaden," Wissenschaftliche Verlagsgesellschaft mbH Stuttgart,
front page to p. V, pp. 2 to 55, 64 to 85, 90 to 97 (2008) (with
English Summary). cited by applicant .
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy
with canakinumab for atherosclerotic disease. N Engl J Med
377(12):1119-31 (publication date Sep. 21, 2017; epublication date
Aug. 27, 2017). cited by applicant .
Ridker, "C-Reactive Protein : A Simple Test to Help Predict Risk of
Heart Attack and Stroke", Circulation: Journal of the American
Heart Association, 2003, 108, e81-e85. cited by applicant .
Riediger, N.D., et al., "A systemic review of the roles of n-3
fatty acids in health and disease." J Am Diet Assoc. 109:668-679.
(2009). cited by applicant .
Rifai, "High-Sensitivity C-Reactive Protein: A Novel and Promising
Marker of Coronary Heart Disease", Clinical Chemistry, 2001, 47(3),
403-411. cited by applicant .
Rise, P., et al., "Effects of simvastatin on the metabolism of
polyunsaturated fatty acids and on glycerolipid, cholesterol, and
de novo lipid synthesis in THP-1 cells." J. Lipid Res. 38:1299-1307
(1997). cited by applicant .
Risk and Prevention Study Collaborative Group, Roncaglioni MC,
Tombesi M, et al. n-3 fatty acids in patients with multiple
cardiovascular risk factors. N Engl J Med. 2013;368(19):1800-8.
cited by applicant .
Rissanen et al., "Fish Oil-Derived Fatty Acids, Docosahexaenoic
Acid and Docosapentaenoic Acid, and the Risk of Acute Coronary
Events The Kuopio Ischaemic Heart Disease Risk Factor Study,"
Circulation. (Nov. 28, 2000)(102):2677-2679
doi:10.1161/01.CIR.102.22.2677. cited by applicant .
Rizzo M, Bemeis K. Low-density lipoprotein size and cardiovascular
risk assessment. Q. J. Med. 2006;99(1): 1-14. cited by applicant
.
Roach, P.D., et al., "The effects of dietary fish oil on hepatic
high density and low density lipoprotein receptor activities in the
rat." Febs Lett., 222: 159-162 (1987). cited by applicant .
Robinson, J.G., et al., "Meta-analysis of the relationship between
non-high-density lipoprotein cholesterol reduction and coronary
heart risk." J Am Coll Cardiol., 53: 316-322 (2009). cited by
applicant .
Roche, H.M., et al., "Effect of long-chain n-3 polyunsaturated
fatty acids on fasting and postprandial triacylglycerol
metabolism." Am J Clin Nutr 71:232S-7S (2000). cited by applicant
.
Roche, H.M., et al., "Long-chain n-3 polyunsaturated fatty acids
and triacylglycerol metabolism in the postprandial state." Lipids
34: S259-S265 (1999). cited by applicant .
Rodriguez, Y., et al., "Long-chain .omega.6 polyunsaturated fatty
acids in erythrocyte phospholipids are associated with insulin
resistance in non-obese type 2 diabetics." Clinica Chimica Acta
354:195-199 (2005). cited by applicant .
Roe MT, Armstrong PW, Fox KAA, et al; Trilogy ACS Investigators.
Prasugrel versus clopidogrel for acute coronary syndromes without
revascularization. N Engl J Med. 367(14):1297-4309 (publication
date Oct. 4, 2012; egublication Aug. 25, 2012). cited by applicant
.
Rogers, P. J., "No effect of n-3 long-chain polyunsaturated fatty
acid (EPA and DHA) supplementation on depressed mood and cognitive
function: a randomised controlled trial" British Journal of
Nutrition, 99:421-431, (2008). cited by applicant .
Rost KL, Roots I. Nonlinear kinetics after high-dose omeprazole
caused by saturation of genetically variable CYP2C19. Hepatology
Jun. 1996 23 (6): 1491-7. cited by applicant .
Rubins, HB, et al., "Distribution of lipids in 8,500 men with
coronary artery disease: Department of Veterans Affairs HDL
Intervention Trial Study Group," Am. J. Cardiol, 75:1196-1201,
(1995). cited by applicant .
Rubins, HB, et al., "Gemfibrozil for the prevention of coronary
heart disease in men with low levels of high-density lipoprotein
cholesterol: Veterans Affairs HDL-C Intervention Trial Study
Group", N. Eng. J. Med., 341:410-418, (1999). cited by applicant
.
Ruiz-Narvaez, E.A., et al., "Abdominal obesity and hyperglycemia
mask the effect of a common APOC3 haplotype on the risk of
myocardial infarction." Am J Clin Nutr 87:1932-8 (2008). cited by
applicant .
Ruocco MJ, Shipley GG. Interaction of cholesterol with
galactocerebroside and galactocerebroside phosphatidylcholine
bilayer membranes. Biophys. J. 1984;46:695-707. cited by applicant
.
Rupp, "Omega-3-Fettsauren in der Sekundarpravention nach
Myokardinfarkt," Clin. Res. Cardiol., vol. 95:Suppl. 6,
Vi/12/-V1-16 (2006)(with English summary). cited by applicant .
Rustan, A.C., et al., "Eicosapentaenoic acid inhibits cholesterol
esterification in cultured parenchymal cells and isolated
microsomes from rat liver." J. Bio. Chem. 263(17):8126-32 (1988).
cited by applicant .
Rustan, A.C., et al., "Eicosapentaenoic acid reduces hepatic
synthesis and secretion of triacylglycerol by decreasing the
activity of acyl-coenzyme A:1,2-diacylglycerol acyltransferase." J.
Lipid Res. 29:1417-1426 (1988). cited by applicant .
Rustan, A.C., et al., "Postprandial decrease in plasma unesterified
fatty acids during n-3 fatty acid feeding is not caused by
accumulation of fatty acids in adipose tissue." Biochimica et
Biophysica Acta 1390.245-25 (1998). cited by applicant .
Ryan, A.M., et al., "Enteral nutrition enriched with
eicosapentaenoic acid (EPA) preserves lean body mass following
esophageal cancer surgery: results of a double-blinded randomized
controlled trial." Ann Surg 249:355-363 (2009). cited by applicant
.
Ryan, A.S., et al., "Clinical overview of algal-docosahexaenoic
acid: effects on triglyceride levels and other cardiovascular risk
factors." Am J Ther., 16:183-192 (2009). cited by applicant .
Sacks, Frank M., "The apolipoprotein story," Atherosclerosis
Supplements, 23-27 (2006). cited by applicant .
Saito et al., "Effects of EPA on coronary artery disease in
hypercholesterolemic patients with multiple risk factors:
Sub-analysis of primary prevention cases from the Japan EPA Lipid
Intervention Study (JELIS)," Atherosclerosis, 200:135-140 (2008).
cited by applicant .
Saito et al., "Results of Clinical Usage of Improved Formulation
(MND-21S) Epadel Capsule 300 with Respect to Hyperlipidemia,"
26(12) Jpn. Pharmacol. Ther. 2047-62 (1998) (with English
abstract). cited by applicant .
Saito, J., et al., "Mechanisms of enhanced production of PGI2 in
cultured rat vascular smooth muscle cells enriched with
eicosapentaenoic acid." Atherosclerosis 131: 219-228 (1997). cited
by applicant .
Sampath H, Ntambi JM., Role of stearoyl-CoA desaturase in human
metabolic disease, Future Lipidol. 2008;3.163-73. cited by
applicant .
Sampath H, Ntambi JM., The Role of stearoyl-CoA desaturase in
obesity, insulin resistance, and inflammation, Ann. NY. Acad. Sci.
2011; 1243:4 7-53. cited by applicant .
Samuels, Martin A., M. D., et al., "Huntington's Disease", Office
Practice of Neurology, (122):654-655, (1996). cited by applicant
.
Sanders, A. Hinds and C.C. Pereira, "Influence of n-3 fatty acids
on blood lipids in normal subjects" Journal of Internal Medicine.
225:99-104,(1989). cited by applicant .
Sanders, et al., "Influence of an algal triacylglycerol containing
docosahexaenoic acid (22:6n-3) and docosapentaenoic acid (22:5n-6)
on cardiovascular risk factors in healthy men and women," British
Journal of Nutrition, 95, 525-531 (2006). cited by applicant .
Sanders, T.A., et al., "Effect of varying the ratio of n-6 to n-3
fatty acids by increasing the dietary intake of .alpha.-linolenic
acid, eicosapentaenoic and docosahexaenoic acid, or both on
fibrinogen and clotting factors VII and XII in persons aged 45-70
y: the OPTILIP Study." Am J Clin Nutr 84:513-22 (2006). cited by
applicant .
Sanders, T.A., et al., "Triglyceride-lowering effect of marine
polyunsaturates in patients with hypertriglyceridemia."
Arterioscler. Thromb. Vasc. Biol. 5:459-465 (1985). cited by
applicant .
Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the
risk of coronary heart disease: 10,158 incident cases among 262,525
participants in 29 Western prospective studies. Circulation
115:450-458, 2007. cited by applicant .
Sasaki J, Miwa T, Odawara M. Administration of highly purified
eicosapentaenoic acid to stain-treated diabetic patients further
improves vascular function. Endocrine J. 2012; 59(4):297-304. cited
by applicant .
Sasaki J, Yokoyama M, Matsuzaki M, et al. Relationship between
coronary artery disease and non-HDL-C, and effect of highly
purified EPA on the risk of coronary artery disease in
hypercholesterolemic patients treated with statins: sub-analysis of
the Japan EPA Lipid Intervention Study (JELIS). J. Atheroscler.
Thromb. 2012;19:194-204. cited by applicant .
Sasaki, Y.F., et al., "Bio-anticlastogenic effects of unsaturated
fatty acids included in fish oil--docosahexaenoic acid,
docosapentaenoic acid, and eicosapentaenoic acid--in cultured
Chinese hamster cells." Mutation Research, 320: 9-22 (1994). cited
by applicant .
Sato et al., "General Pharmacological Studies on 5 8 11 14 17
Eicosapentaenoic Acid Ethyl Ester EPA-E", Folia Pharmacol JPN, 94
(1), 35-47. (1989) (with English abstract). cited by applicant
.
Sato, "Effects of Highly Purified Ethyl
All-cis-5,8,11,14,17-icosapentaenoate (EPA-E) on Rabbit Platelets,"
Biol. Pharm. Bull., 16(4)362-367 (1993). cited by applicant .
Satoh et al., "Highly purified eicosapentaenoic acid reduces
cardio-ankle vascular index in association with decreased serum
amyloid A-LDL in metabolic syndrome," Hypertension Research (2009)
(32):1004-1008. cited by applicant .
Satoh, N., et al., "Purified eicosapentaenoic acid reduces small
dense LDL, remnant lipoprotein particles, and C-reactive protein in
metabolic syndrome." Diabetes Care, 30(1): 144-146 (2007). cited by
applicant .
Satoh-Asahara N, Shimatsu A, Sasaki Y, Nakaoka H, Himeno A, Tochiya
M, Kono S, Takaya T, Ono K, Wada H, Suganami T, Hasegawa K, Ogawa
Y., "Highly purified eicosapentaenoic acid increases interleukia-10
levels of peripheral blood monocytes in obese patients with
dyslipidemia." Diabetes Care. 2012;35(12):2631-2639. cited by
applicant .
Schaefer, E.J., et al., "Effects of eicosapentaenoic acid,
docosahexaenoic acid, and olive oil on cardiovascular disease risk
factors [abstract 20007]." Circulation, 122:A20007 (2010) (Abstract
only). cited by applicant .
Schectman, G. & Hiatt, J., "Drug therapy for
hypercholesterolemia in patients with cardiovascular disease:
factors limiting achievement of lipid goals", Am. J. Med.,
100:197-204, (1996). cited by applicant .
Schectman, G., et al., "Dietary fish oil decreases
low-density-lipoprotein clearance in nonhuman primates." Am J Clin
Nutr., 64:215-221 (1996). cited by applicant .
Schectman, G., et al., "Heterogeneity of Low Density Lipoprotein
Responses to Fish-Oil Supplementation in Hypertriglyceridemic
Subjects." Arterioscler. Thromb. Vasc. Biol. 9:345-354 (1989).
cited by applicant .
Schmidt, E.B., et al., "Lipoprotein-associated phospholipase A2
concentrations in plasma are associated with the extent of coronary
artery disease and correlate to adigose tissue levels of marine n-3
fatty acids." Atherosclerosis 196: 420-424 (2008). cited by
applicant .
Schmitz PG, McCloud LK, Reikes ST, et al. Prophylaxis of
hemodialysis graft thrombosis with fish oil: double-blind,
randomized, prospective trial. J. Am. Soc. Nephrol. Jan. 2002 13
(1): 184-90. cited by applicant .
Schmitz, G., et al., "The opposing effects of n-3 and n-6 fatty
acids." Progress in Lipid Research, 47:147-155 (2008). cited by
applicant .
Schreiner et al., Lipoprotein[a] as a Risk Factor for Preclinical
Atherosclerosis, 13 Atherosclerosis, Thrombosis & Vascular
Biology 826, 826 (1993). cited by applicant .
Schuirmann, D.J. A comparison of the two one-sided tests procedure
and the power approach for assessing the equivalence of average
bioavailability. J. Pharmacokinet. Biopharm. 15, 657-680 (1987).
cited by applicant .
Schunkert H, Konig IR, Kathiresan S, et al. Large-scale association
analysis identifies 13 new susceptibility loci for coronary artery
disease. Nat Genet. 2011;43(4):333-8. cited by applicant .
Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a
monoclonal antibody to PCSK9, on long-term cardiovascular outcomes
following acute coronary syndromes: rationale and design of the
ODYSSEY outcomes trial. Am Heart J 168(5):682-9 (publication date
Nov. 2014, epublication date Aug. 7, 2017). cited by applicant
.
Schwarz, S., et al., "Lycopene inhibits disease progression in
patients with benign prostate hyperplasia." J. Nutr. 138: 49-53
(2008). cited by applicant .
Schwellenbach et al., "The Triglyceride-Lowering Effects of a
Modest Dose of Docosahexaenoic Acid Alone Versus in Combination
with Low Dose Eicosapentaenoic Acid in Patients with Coronary
Artery Disease and Elevated Triglycerides." J. Am. Coll. Nutr.
25(6):480-485 (2006). cited by applicant .
Segrest et al., Structure of Apolipoprotein B-100 in Low Density
Lipoproteins, J. Lipid Res. 42(9):1346-1367 (2001). cited by
applicant .
Self-Medlin Y, Byun J, Jacob RF, Mizuno Y, Mason RP. Glucose
promotes membrane cholesterol crystalline domain formation by lipid
peroxidation. Biochim. Biophys. Acta. 2009; 1788(6): 1398-1403.
cited by applicant .
Serhan C, Chiang N, Van Dyke T. Resolving inflammation: dual
anti-inflammatory and pro-resolution lipid mediators. Nat Rev
Immunol. 2008; 8:3449-361. cited by applicant .
Serhan, C.N., et al., "Resolvins: a family of bioactive products of
omega-3 fatty acid transformation circuits initiated by aspirin
treatment that counter proinflammation signals." J. Exp. Med.
196:1025-1037 (2002). cited by applicant .
Sevanian A, Ursini F. Lipid peroxidation in membranes and
low-density lipoproteins: similarities and differences. Free Radic.
Biol. Med. 2000;29(3-4):306-311. cited by applicant .
Shah, S. et al., "Eicosapentaenoic Acid (EPA) as an Adjunct in the
Treatment of Schizophrenia", Schizophrenia Research, vol. 29, No.
1/02 (1998). cited by applicant .
Shan, Z., et al., "A combination study of spin-trapping, LC/ESR and
LC/MS on carbon-centred radicals formed from lipoxygenase-catalysed
peroxidation of eicosapentaenoic acid." Free Radical Research,
43(1):13-27 (2009). cited by applicant .
Sherratt SCR, Mason RP. Eicosapentaenoic acid and docosahexaenoic
acid have distinct membrane locations and lipid interactions as
determined by X-ray diffraction. Chem Phys Lipids 212:73-9
(publication date May 2018, epublication date Jan. 31, 2018). cited
by applicant .
Shimizu et al., "Effects of Highly Purified Eicosapentaenoic Acid
on Erythrocyte Fatty Acid Composition and Leukocyte and Colonic
Mucosa Leukotriene B4 Production in Children with Ulcerative
Colitis," J. Pediatr. Gastroenterol. Nutr., vol. 37, No. 5, pp.
581-585 (2003). cited by applicant .
Shimizu, H., et al., "Long-term effect of eicosapentaenoic acid
ethyl (EPA-E) on albuminuria of non-insulin dependent diabetic
patients." Diabetes Research and Clinical Practice 28: 35-40
(1995). cited by applicant .
Shimokawa H, Flavahan NA, Vanhoutte PM. Loss of endothelial
pertussis toxin-sensitive g protein function in atherosclerotic
porcine coronary arteries. Circulation. 1991;83:652-660. cited by
applicant .
Shinozaki K. et al., "The long-term effect of Eicosapentaenoic acid
on serum levels of lipoprotein (a) and lipids in patients with
vasciular disease" J Atheroscler Thromb. 2(2):207-9 (1996). cited
by applicant .
Shishehbor MH, Brenna ML, Aviles RJ, Fu X, Penn MS, Sprecher DL,
Hazen SL. Statins promote potent systemic antioxidant effects
through specific inflammatory pathways. Circulation.
2003;108(4):426-431. cited by applicant .
Sicherer et al., "Prevalence of seafood allergy in the United
States determined by a random telephone survey," J. Allergy Clin.
Immunol., 114(1):159-165 (Jul. 2004). cited by applicant .
Sierra, S., et al., "Dietary eicosapentaenoic acid and
docosahexaenoic acid equally incorporate as decosahexaenoic acid
but differ in inflammatory effects." Nutrition 24: 245-254 (2008).
cited by applicant .
Silvers, Karen M., et al., "Randomised double-blind
placebo-controlled trial of fish oil in the treatment of
depression", Prostagandins, Leukotrienes and Essential Fatty Acids,
72:211-218, (2005). cited by applicant .
Simoens, C.M., et al., "Inclusion of 10% fish oil in mixed
medium-chain triacylglycerol--long chain triacylglycerol emulsions
increases plasma triacylglycerol clearance and induces rapid
eicosapentaenoic acid (20:5n-3) incorporation into blood cell
phospholipids." Am J Clin Nutr 88: 282-8 (2008). cited by applicant
.
Simon, Joel A., et al., "Serum Fatty Acids and the Risk of Coronary
Heart Disease", American Journal of Epidemiology, 142(5):469-476,
(1995). cited by applicant .
Simopolous, The Importance of the Omega-6/Omega-3 Fatty Acid Ratio
in Cardiovascular Disease and Other Chronic Diseases, Exp. Biol.
Med, 233:674-688 (Jun. 1, 2008)(available online Jun. 1, 2008).
cited by applicant .
Simopoulos, "Omega-3 fatty acids in health and disease and in
growth and development," Am. J. Clin. Nutr. 54:438-63 (1991). cited
by applicant .
Singer, Peter, "Fluvastatin plus fish oil are more effective on
cardiovascular risk factors than fluvastatin alone," Letter to the
Editor, Prostaglandinis, Leukotrienes and Essential Fatty Acids,
vol. 72, pp. 379-380 (2005). cited by applicant .
Singh, R.B., et al., "Randomized, double-blind, placebo-controlled
trial of fish oil and mustard oil in patients with suspected acute
myocardial infarction: the Indian experiment of infarct
survival--4." Cardiovascular Drugs and Therapy 11:485-491 (1997).
cited by applicant .
Sirtori, C.R., et al., "One-year treatment with ethyl esters of n-3
fatty acids in patients with hypertriglyceridemia and glucose
intolerance--Reduced triglyceridemia, total cholesterol and
increased HDL-C." Atherosclerosis 137: 419-427 (1998). cited by
applicant .
Skinner JS, Cooper A, & Feder GS and on behalf of the Guideline
Development Group. "Secondary prevention for patients following a
myocardial infarction; summary of NICE guidance," Heart, 93:862-864
(2007). cited by applicant .
Slides for the Oct. 16, 2013 Meeting of the Endocrinologic and
Metabolic Drugs Advisory Committee, (158 pages). cited by applicant
.
Smith et al., Pharmacokinetics and Pharmacodynamics of Epoetin
Delta in Two Studies in Health Volunteers and Two Studies in
Patients with Chronic Kidney Disease, Clinical Therapeutics/vol.
29, pp. 1368-1380 (2007). cited by applicant .
Sniderman A, Kwiterovich PO. Update on the detection and treatment
of atherogenic low-density lipoproteins. Curr. Opin. Endocrinol.
Diabetes Obes. Apr. 20, 2013;20:140-147. cited by applicant .
Sohma, R., et al., "Protective effect of n-3 polyunsaturated fatty
acid on primary culture of rat hepatocytes without glycemic
alterations." Journal of Gastroenterology and Hepatology 22:
1965-1970 (2007). cited by applicant .
Spector, A.A., "Arachidonic acid cytochrome P450 epoxygenase
pathway." Journal of Lipid Research, 50: S52-S56 (2009) (published
online on Oct. 23, 2008.). cited by applicant .
Spector, A.A., et al., "Epoxyeicosatrienoic acids (EETs):
metabolism and biochemical function." Progress in Lipid Research
43: 55-90 (2004). cited by applicant .
Springer, T.A., "Traffic signals for lymphocyte recirculation and
leukocyte emigration: The multistep paradigm." Cell, 76: 301-314
(1994). cited by applicant .
Squires, RW, et al., "Low-dose, time release nicotinic acid:
effects in selected patients with low concentrations of high
density lipoprotein cholesterol", Mayo Clinic Proc., 67:855-860,
(1992). cited by applicant .
Srinivas, et al., "Controlled release of lysozyme from succinylated
gelatin microspheres," J. Biomater. Sci., Polymer Ed., vol.
12(2):137-148 (2001). cited by applicant .
Stalenhoef, A.F.H., et al., "The effect of concentrated n-3 fatty
acids versus gemfibrozil on plasma lipoproteins, low density
lipoprotein heterogeneity and oxidizability in patients with
hypertriglyceridemia." Atherosclerosis 153: 129-138 (2000). cited
by applicant .
Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of trig
lyceride level, lowdensity lipoprotein particle diameter, and risk
of myocardial infarction. JAMA. 1996;276:882-888. cited by
applicant .
Stancu et al., "Statins: Mechanism of Action and Effects," Journal
of Cellular and Molecular Medicine (2001), 5(4), 378-387. cited by
applicant .
Stark, K.D. & Holub, B.J., Differential eicosapentaenoic acid
elevations and altered cardiovascular disease risk factor responses
after supplementation with docosahexaenoic acid in postmenopausal
women receiving and not receiving hormone replacement therapy, Am.
J. Clin. Nutr., vol. 79, pp. 765-73 (2004). cited by applicant
.
Stark, K.D., "The percentage of n-3 highly unsaturated fatty acids
in total HUFA as a biomarker for omega-3 fatty acid status in
tissues." Lipids 43:45-53 (2008). cited by applicant .
Stark, K.D., et al., "Effect of a fish-oil concentrate on serum
lipids in postmenopausal women receiving and not receiving hormone
replacement therapy in a placebo-controlled, double-blind trial."
Am J Clin Nutr 72:389-94 (2000). cited by applicant .
Steg PG, Bhatt DL, Wilson PWF, et al; REACH Registry Investigators.
One-year cardiovascular event rates in outpatients with
atherothrombosis. JAMA. 297(11):1197-1206 (publication date May 21,
2007). cited by applicant .
Stein et al., "Effect of Statin Therapy on Remnant Lipoprotein
Cholesterol Levels in Patients with Combined Hyperlipidemia,"
Arteriosclerosis, Thrombosis and Vascular Biology, vol. 21, pp.
2026-2031(Dec. 1, 2001). cited by applicant .
Steinberg D, Witztum JL. Is the oxidative modification hypothesis
relevant to human atherosclerosis? Do the antioxidant trials
conducted to date refute the hypothesis? Circulation.
2002;105:2107-2111. cited by applicant .
Steinberg D. Lewis A. Conner Memorial Lecture: Oxidative
modification of LDL and atherogenesis. Circulation.
1997;95(4):1062-1071. cited by applicant .
Stepp DW, Ou J, Ackerman AW, Welak S, Klick D, Pritchard KA, Jr.
Native ldl and minimally oxidized ldl differentially regulate
superoxide anion in vascular endothelium in situ. Am. J. Physiol.
2002;283:H750-H759. cited by applicant .
Sternbach "The Glasgow Coma Scale." The Journal of Emergency
Medicine, 19(1):67-71 (Feb. 8, 2000). cited by applicant .
Stiles, FDA approves EPA-only omega-3 PUFA capsule for high TG,
http://www.medscape.com/viewarticle/791268, accessed Dec. 17, 2014
(1 page). cited by applicant .
Stitziel N, Stirrups K, Masca N, et al. Supplement to: Coding
variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary
disease. N Engl J Med. DOI: 10.1056/NEJMoa1507652; 2016. cited by
applicant .
Stojancevic et al., "The impact of farnesoid X receptor activation
on intestinal permeability in inflammatory bowel disease," Can. J
Gastroenterol. 26(9):631-637 (2012). cited by applicant .
Stoll, Andrew L. et al., "Omega 3 Fatty Acids in Bipolar Disorder",
Arch. Gen. Psychiatry, 56:407-412, (May 1999). cited by applicant
.
Stone NJ, Robinson J, Lichtenstein AH, et al. ACC/AHA Prevention
Guideline: 2013 ACC/AHA Guideline on the Treatment of Blood
Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in
Adults: A Report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. Circulation.
2014;129:S46-S48. cited by applicant .
Su, Kuan-Pin, et al., "Omega-3 Fatty Acids in Major Depressive
Disorder a Preliminary Double-Blind, Placebo-Controlled Trial",
European Neuropsychopharmacology, 13:267-271, (2003). cited by
applicant .
Sugiyama et al., "A Comparison of the Hypotensive Effects of
Eicosapentaenoic Acid Ethyl (EPA) on Three Diseases (Occluded
Arteriosclerosis, Hyperlipidemia, and These Two Diseases Combined)
P2-504 Abstract," Annual Meeting of the Japanese Society of
Pharmaceutical Health Care and Sciences 20:473 (Nov. 2010) (with
English translation)(3 pages). cited by applicant .
Sugiyama, E., et al., "Eicosapentaenoic acid lowers plasma and
liver cholesterol levels in the presence of peroxisome
proliferators-activated receptor alpha." Life Sciences, 83:19-28
(2008). cited by applicant .
Superko et al., "Lipid Management to Reduce Cardiovascular Risk: A
New Strategy is Reguired," Circulation, 117:560-568 (2008). cited
by applicant .
Surette, M.E., et al., "Dependence on dietary cholesterol for n-3
polyunsaturated fatty acid induced changes in plasma cholesterol in
the Syrian hamster." J Lipid Res., 33:263-271 (1992). cited by
applicant .
Surette, M.E., et al., "Evidence for mechanisms of the
hypotriglyceridemic effect of n-3 polyunsaturated fatty, acids."
Biochimica et Biophysic Acta, 1126: 199-205 (1992). cited by
applicant .
Tagawa H, Shimokawa H, Tagawa T, et al. Long-term treatment with
eicosapentaenoic acid augments both nitric oxide-mediated and
non-nitric oxide-mediated endothelium-dependent forearm
vasodilatation in patients with coronary artery disease. J
Cardiovasc Pharmacol 33(4):633-40, 1999. cited by applicant .
Takaki A, Umemoto S, Ono K, Seki K, Ryoke T, Fujii A, Itagaki T,
Harada M, Tanaka M, Yonezawa T, Ogawa H, Matsuzaki M. Add-on
therapy of epa reduces oxidative stress and inhibits the
progression of aortic stiffness in patients with coronary artery
disease and statin therapy: A randomized controlled study. J.
Atheroscler. Thromb. 2011;18:857-866. cited by applicant .
Takaku et al., Study on the Efficacy and Safety of Ethyl
Icosapentate (MND-21) in Treatment of Hyperlipidemia Based on a
Long-Term Administration Test, 7 J. Clin. Ther. Med. 191 (1991)
(with English Translation)(27 pages). cited by applicant .
Talayero BG, Sacks FM. The role of triglycerides in
atherosclerosis. Curr. Cardiol. Rep. 2011;13:544-552. cited by
applicant .
Tamura, et al., "Study of the Clinical Usefulness of Ethyl
Icosapentate (MND-21) in Long-Term Treatment of Hyperlipaemic
Patients." J Clin Thera & Medicines, 7:1817-1834 (1991). cited
by applicant .
Tanaka et al., "Genome-Wide Association Study of Plasma
Polyunsaturated Fatty Acids in the InCHIANTI Study." PLoS Genetics
5(1):1-8 (Jan. 2009). cited by applicant .
Tanaka et al., "Suppression of prostaglandin synthesis by
arachidonic acid or eicosapentaenoic acid in a macrophage-like cell
line, RAW 264.7, treated with LPS," Biol. Pharm. Bull.,
22(10):1057-7 (1999). cited by applicant .
Tanaka et al., "Administration of high dose eicosapentaenoic acid
enhances anti-inflammatory properties of high-density lipoprotein
in Japanese patients with dyslipidemia," Atherosclerosis,
237(2):577-83 (Dec. 2014). cited by applicant .
Tanaka et al., "Eicosapentaenoic Acid-Enriched High-Density
Lipoproteins Exhibit Anti-Atherogenic Properties," Circ. J., doi:
10.1253/circj.CJ-17/0294. [Epub ahead of print] (Jun. 23, 2017)(6
pages). cited by applicant .
Tanaka, K.T., et al., "Reduction in the recurrence of stroke by
eicosapentaenoic acid for hypercholesterolemic
patients--Subanalysis of the JELIS trial." Stroke, 39(7):2052-8
(2008). cited by applicant .
Tatarczyk, et al., "Analysis of long-chain .omega.-3 fatty acid
content in fish-oil supplements," Wien Klin Wochenschr, 119/13-14:
417-422 (2007). cited by applicant .
Tatsuno et al., Efficacy and safety of TAK-085 compared with
eicosapentaenoic acid in Japanese subjects with
hypertriglyceridemia undergoing lifestyle modification: The omega-3
fatty acids randomized double-blind (ORL) study, J. Clin. Lipid;
vol. 7(6), pp. 615-625 (Sep. 12, 2013). cited by applicant .
Taylor et al., "Fish allergy: fish and products thereof," Journal
Food Science (2004) 69.8 R175-R180. cited by applicant .
Taylor, A.J., et al., "Arterial Biology for the Investigation of
the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a
double-blind, placebo-controlled study of extended-release niacin
on atherosclerosis progression in secondary prevention patients
treated with statins", Circulation, 110:3512-3517, (2004). cited by
applicant .
Tedgui, A., et al., "Anti-inflammatory mechanisms in the vascular
wall." Circ. Res. 88:877-887 (2001). cited by applicant .
Teissier E, Nohara A, Chinetti G, Paumelle R, Cariou B, Fruchart
JC, Brandes RP, Shah A, B. Steels Peroxisome proliferator-activated
receptor alpha induces NADPH oxidase activity in macrophages,
leading to the generation of LDL with PPAR-alpha activation
properties. Circ. Res. 2004;95(12):1174-1182. cited by applicant
.
Teramoto T, Sasaki J, Ishibashi S, et al. Diagnosis of
atherosclerosis. Executive Summary of the Japan Atherosclerosis
Society (JAS) Guidelines for the Diagnosis and Prevention of
Atherosclerotic Cardiovascular Diseases in Japan--2012 Version. J
Atheroscler Thromb. 2014;21(4):296-8. Electronic publication Dec.
10, 2013. cited by applicant .
Terano, et al., "Effect of Oral Administration of Highly Purified
Eicosapentaenoic Acid on Platelet Function, Blood Viscosity and Red
Cell Deformability in Healthy Human Subjects," Atherosclerosis, 46,
321-331 (1983). cited by applicant .
The TG and HDL Working Group of the Exome Sequencing Project,
National Heart, Lung, and Blood Institute. Loss-of-function
mutations in APOC3, triglycerides, and coronary disease. N Engl J
Med. 2014;371(1):22-31. cited by applicant .
Theilla, M., et al., "A diet enriched in eicosapentaenoic acid,
gamma-linolenic acid and antioxidants in the prevention of new
pressure ulcer formation in critically ill patients with acute lung
injury: A randomized, prospective, controlled study." Clinical
Nutrition 26: 752-757 (2007). cited by applicant .
Theobald et al., "LDL Cholesterol-Raising Effect of Low-Dose
Docosahexaenoic Acid in Middle-Aged Men and Women," Am. J. Clin.
Nutr. 79:558-63 (2004). cited by applicant .
Thies, F., et al., "Association of n-3 polyunsaturated fatty acids
with stability of atherosclerotic plaques: a randomised controlled
trial." Lancet 361: 477-85 (2003). cited by applicant .
Thies, F., et al., "Dietary supplementation with eicosapentaenoic
acid, but not with other long-chain n-3 or n-6 polyunsaturated
fatty acids, decreases natural killer cell activity in healthy
subjects aged >55 y." Am J Clin Nutr 73:539-48 (2001). cited by
applicant .
Third Report of the NCep Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel III) Final Report, NIH Publication No. 02-5215 Sep. 2002 (220
pages in three parts). cited by applicant .
Thorwest M, Balling E, Kristensen SD, et al. Dietary fish oil
reduces microvascular thrombosis in a porcine experimental model.
Thromb. Res. Jul. 2000 99 (2): 203-8. cited by applicant .
Thygesen K., Alpert J., Jaffe A., et al. Third Universal Definition
of Myocardial Infarction. J Am Coll Cardiol. 2012;60(16):1581-1598.
cited by applicant .
Tilg H, Moschen AR. Inflammatory Mechanisms in the Regulation of
Insulin Resistance. Mol. Med. 2008;14(3-4):222-231. cited by
applicant .
Tirosh et al., "Changes in Triglyceride Levels and Risk for
Coronary Heart Disease in Young Men," American College of
Physicians, pp. 377-385 (2007). cited by applicant .
Torrejon, C. et al., "n-3 Fatty acids and cardiovascular disease:
Actions and molecular mechanisms," Prostaglandins Leukotrienes
& Essent. Fatty Acids, doi:10.1016/j.plefa.2007.10.014 (2007).
cited by applicant .
Toth PP, Granowitz C, Hull M, Liassou D, Anderson A, Philip S. High
Triglycerides are associated with increased cardiovascular events,
medical costs, and resource use: A real-world administrative claims
analysis of statin-treated patients with high residual
cardiovascular risk. Journal of the American Heart Association,
7(15):e008740 (publication date Jul. 25, 2018; epublication Aug. 7,
2018). cited by applicant .
Transcript from Oct. 16, 2013 Meeting of the Endocrinologic and
Metabolic Drugs Advisory Committee, 76 pages. cited by applicant
.
TREND-HD Investigators, Randomized controlled trial of
ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD
study, Arch Neurol., vol. 65(12): 1582-9 (2008). cited by applicant
.
Tribble DL, Holl LG, Wood PD, Krauss RM. Variations in oxidative
susceptibility among six low density lipoprotein subfractions of
differing density and particle size. Atherosclerosis.
1992;93(3):189-199. cited by applicant .
Tribble DL, Rizzo M, Chait A, Lewis DM, Blanche PJ, Krauss RM.
Enhanced oxidative susceptibility and reduced antioxidant content
of metabolic precursors of small, dense low-density ligogroteins.
Am. J. Med. 2001;110(2):103-110. cited by applicant .
Trilipix Package Insert (Sep. 2010)(10 pages). cited by applicant
.
Tsimikas S, Witztum JL, Miller ER, Sasiela WJ, Szarek M, Olsson AG,
Schwartz GG. High-dose atorvastatin reduces total plasma levels of
oxidized phospholipids and immune complexes present on
apolipoprotein B-1 00 in patients with acute coronary syndromes in
the MIRACL trial. Circulation. 2004;110(11):1406-1412. cited by
applicant .
Tsuruta K., et al.,"Effects of purified eicosapentaenoate ethyl
ester on fibriolytic capacity in patients with stable coronary
artery disease and lower extremity ischaemia" Coron Artery Dis.
7(11):837-42 (Nov. 1996). cited by applicant .
Tulenko TN, Chen M, Mason PE, Mason RP. Physical effects of
cholesterol on arterial smooth muscle membranes: Evidence of
immiscible cholesterol domains and alterations in bilayer width C
during atherogenesis. J. Lipid Res. 1998;39:947-956. cited by
applicant .
Tungsiripat, et al., "Dyslipidemia in HIV patients," Cleveland
Clinic Journal of Medicine, v. 72, No. 12 (2005). cited by
applicant .
Turini et al., "Short-term fish oil supplementation improved innate
immunity, but increased ex vivo oxidation of LDL in man--a pilot
study." Eur. J. Nutr. 40:56-65 (2001). cited by applicant .
U.S. Appl. No. 14/245,499, filed Apr. 4, 2014 (now abandoned)(43
pages). cited by applicant .
Ullian, M.E., "Fatty acid inhibition of angiotensin II-stimulated
inositol phosphates in smooth muscle cells." Am J Physiol Heart
Circ Physiol (1996). cited by applicant .
Urakaze, Masaharu, et al., "Infusion of emulsified
trieicosapentaenoylglycerol into rabbits. The effects on platelet
aggregation, polymorphonuclear leukocyte adhesion, and fatty acid
composition in plasma and platelet phospholipids", Thromb. Res.,
44(5):673-682 (1986). cited by applicant .
Urquhart et al., "Profile of eicosanoids produced by human
saphenous vein endothelial cells and the effect of dietary fatty
acids," Prostaglandins Leukot. Essent. Fatty Acid, 65(1):15-22
(2001). cited by applicant .
US Food and Drug Administration and Dept of Health and Human
Services. Substances affirmed as generally recognized as safe:
Menhaden Oil. Fed Register, 62:30751-30757 (1997). cited by
applicant .
Vaagenes et al., "The Hypolipidaemic Effect of EPA is Potentiated
by 2- and 3-Methylation." In P. Quant & S. Eaton (eds.) Current
Views of Fatty Acid Oxidation and Ketogenesis from Organelles to
Point Mutations; Advances in Experimental Medicine and Biology,
vol. 466 , pp. 221-226 (1999). cited by applicant .
Vaddadi, K.S., et al., "A Randomised, Placebo-Controlled,
Double-Blind Study of Treatment of Huntington's Disease with
Unsaturated Fatty Acids", Clinical Neuroscience and NeuroBathology,
13(1):29-33, (Jan. 2002). cited by applicant .
Vaduganathan M, Venkataramani AS, Bhatt DL. Moving toward global
primordial prevention in cardiovascular disease: The heart of the
matter. J Am Coll Cardiol 2015;66(14):1535-7. cited by applicant
.
Van der Steeg, W.A., et al., "High-density lipoprotein cholesterol,
high-density lipoprotein particle size, and apolipoprotein A-I:
Significance for cardiovascular risk--the IDEAL and EPIC-Norfolk
studies." J. Am. Coll. Cardiol. 51;634-642 (2008). cited by
applicant .
Van Do et al., "Allergy to fish parvalbumins: Studies on the
cross-reactivity of allergens from 9 commonly consumed fish,"
Journ. Allergy & Clin. Immunol., 16(6):1314-1320 (Dec. 1,
2005). cited by applicant .
Van Wijk et al. Rosiglitazone improves postprandial triglyceride
and free fatty acid metabolism in type 2 diabetes. Diabetes Care,
vol. 28, No. 4, (2005) pp. 844-849. cited by applicant .
Varbo A, Benn M, Tybj.ae butted.rg-Hansen A, Nordestgaard BG. Reply
to letters regarding article, "Elevated remnant cholesterol causes
both low-grade inflammation and ischemic heart disease, whereas
elevated low-density lipoprotein cholesterol causes ischemic heart
disease without inflammation". Circulation. 2014;129:e656. cited by
applicant .
Varbo et al., Remnant Cholesterol as a Causal Risk Factor for
Ischemic Heart Disease, J. Am. Coll. Cardiol., vol. 61(4), pp.
427-36 (2013). cited by applicant .
Varbo et al., Remnant cholesterol as a cause of ischemic heart
disease: Evidence, definition, measurement, atherogenicity, high
risk patients, and present and future treatment, Pharmacol. Ther.,
vol. 141(3), pp. 358-367 (2014). cited by applicant .
Vascepa [package insert], Bedminster, NJ: Amarin Pharma Inc.; Jul.
2012. (12 pages). cited by applicant .
Vascepa [package insert]. Bedminster, NJ: Amarin Pharma Inc.; Nov.
2013. (11 pages). cited by applicant .
Vasudevan et al., "Effective Use of Combination of Lipid Therapy",
Curr. Atheroscl. Rep., vol. 8, pp. 76-84 (2006). cited by applicant
.
Vedin, I., et al., "Effects of docosahexaenoic acid-rich n-3 fatty
acid supplementation on cytokine release from blood mononuclear
leukocytes: the OmegAD study." Am J Clin Nutr 87:1616-22 (2008).
cited by applicant .
Velliquette et al., "Regulation of human stearoyl-CoA desaturase by
omega-3 and omega-6 fatty acids: Implications for the dietary
management of elevated serum triglycerides," Journal of Clinical
Lipdology. (2009) 3:281-288. cited by applicant .
Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G,
Brovkovych V, Fellin R, Malinski T. Effect of native and oxidized
low-density lipoprotein on endothelial nitric oxide and superoxide
production : Key role of 1-arginine availability. Circulation.
2000;101:1261-1266. cited by applicant .
Verma S, Leiter LA, Bhatt DL. CANTOS ushers in a new calculus of
inflammasome targeting for vascular protection-and maybe more. Cell
Metab 26(5):703-5 (publication date Nov. 7, 2017; epublication date
Oct. 19, 2017). cited by applicant .
Vidal F, Colome C, Martinez-Gonzalez J, Badimon L. Atherogenic
concentrations of native low density lipoproteins down-regulate
nitric-oxide-synthase mma and protein levels in endothelial cells.
Eur. J. Biochem. 1998;252:378-384. cited by applicant .
Vidgren, H.M., et al., "Incorporation of n-3 fatty acids into
plasma lipid fractions, and erythrocyte membranes and platelets
during dietary supplementation with fish, fish oil, and
docosahexaenoic acid-rich oil among healthy young men." Lipids 32:
697-705 (1997). cited by applicant .
Virani et al., "The Role of Lipoprotein-associated Phospholipase A2
as a marker for atherosclerosis" Curr. Atheroscler. Rep. 9[2):
97-103 (2007). cited by applicant .
Volcik, K.A., et al., "Peroxisome proliferator-activated receptor
agenetic variation interacts with n-6 and long-chain n-3 fatty acid
intake to affect total cholesterol and LDL-cholesterol
concentrations in the Atherosclerosis Risk in Communities Study."
Am J Clin Nutr 87:1926-31 (2008). cited by applicant .
Von Schacky C, Baumann K, Angerer P. The effect of n-3 fatty acids
on coronary atherosclerosis: results from SCIMO, an angiographic
study, background and implications. Lipids 2001 36 Suppl: S99-102.
cited by applicant .
Von Schacky, C., "A review of omega-3 ethyl esters for
cardiovascular prevention and treatment of increased blood
triglyceride levels." Vascular Health and Risk Management 2(3):
251-262 (2006). cited by applicant .
Von Schacky, C., et al., "The Effect of Dietary .omega.-3 Fatty
Acids on Cornoray Atherosclerosis: A Randomized, Double-Blind,
Placebo-Controlled Trial", American College of Physicians-American
Society of Internal Medicine, 130(7):554-562, (1999). cited by
applicant .
Wada, M., et al., "Enzymes and receptors of prostaglandin pathways
with arachidonic acid-derived versus eicosapentaenoic acid-derived
substrates and products." J. Biol. Chem. 282(31): 22254-22266
(2007). cited by applicant .
Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M. Improvement
of nitric oxide-dependent vasodilation by hmg-coa reductase
inhibitors through attenuation of endothelial superoxide anion
formation. Arterioscler. Thromb. Vasc. Biol. 2000;20:61-69. cited
by applicant .
Walker G, Mandagere A, Dufton C, et al. The pharmacokinetics and
pharmacodynamics of warfarin in combination with ambrisentan in
healthy volunteers. Br. J. Clin. Pharmacol. May 2009 67 (5):
527-34. cited by applicant .
Wall R, Ross RP, Fitzgerald G, Stanton C. Fatty acids from fish:
the anti-inflammatory potential of long-chain omega-3 fatty acids.
Nutr Rev. 2010; 68:280-289. cited by applicant .
Walldius, G., et al., "Editorial: Rationale for using
apolipoprotein B and apolipoprotein A-I as indicators of cardiac
risk and as targets for lipid-lowering therapy." European Heart
Journal 26, 210-212 (2005). cited by applicant .
Walter MF, Jacob RF, Bjork RE, Jeffers B, Buch J, Mizuno Y, Mason
RP. Circulating lipid hydroperoxides predict cardiovascular events
in patients with stable coronary artery disease: the PREVENT study.
J. Am. Coll. Cardiol. 2008;51(12):1196-1202. cited by applicant
.
Walter MF, Jacob RF, Jeffers B, Ghadanfar MM, Preston GM, Buch J,
Mason RP. Serum levels of TBARS predict cardiovascular events in
patients with stable coronary artery disease: A longitudinal
analysis of the PREVENT study. J. Am. Coll. Cardiol.
2004;44(10):1996-2002. cited by applicant .
Wander, R.C., et al., "Influence of long.chain polyunsaturated
fatty acids on oxidation of low density lipoprotein."
Prostaglandins, Leukotrienes and Essential Fatty Acids
59(2):143-151 (1998). cited by applicant .
Wang Q, Liang X, Wang L, Lu X, Huang J, Cao J, Li H, Gu D. Effect
of omega-3 fatty acids supplementation on endothelial function: A
meta-analysis of randomized controlled trials. Atherosc. 2012;
221:563-543. cited by applicant .
Wang, C., et al., "n-3 Fatty acids from fish or fish-oil
supplements, but not .alpha.-linolenic acid, benefit cardiovascular
disease outcomes in primary- and secondary-prevention studies: a
systematic review." Am J Clin Nutr 84:5-17 (2006). cited by
applicant .
Wang, L., et al., "Triglyceride-rich lipoprotein lipolysis releases
neutral and oxidized FFAs that induce endothelial cell
inflammation." J. Lipid Res. 50:204-213 (2009). cited by applicant
.
Warren, Stephen T., "The Expanding World of Trinucleotide Repeats",
Science, 271:1374-1375, (1996). cited by applicant .
Wassmann S, Laufs U, Muller K, Konkol C, Ahlbory K, Baumer AT, Linz
W, Bohm M, Nickenig G. Cellular antioxidant effects of atorvastatin
in vitro and in vivo. Arterioscler. Thromb. Vasc. Biol.
2002;22:300-305. cited by applicant .
Watanabe et al., "Bile acids lower triglyceride levels via a
pathway involving FXR, SHP, and SREBP-1c," J Clin Invest. 113(10):
1408-1418 (May 2004). cited by applicant .
Watanabe T, Ando K, Daidoji H, et al. A randomized controlled trial
of eicosapentaenoic acid in patients with coronary heart disease on
statins. J Cardiol 70(6):537-44 (publication date Dec. 2017;
epublication date Aug. 31, 2017). cited by applicant .
Watanabe, Ikuyoshi, et al., "Usefulness of EPA-E (eicosapentaenoic
acid ethyl ester) in preventing neointimal formation after vascular
injury", Kokyu to Junkan, 42(7):673-677 0994) (with English
summary). cited by applicant .
Weaver, K.L., et al., "Effect of Dietary Fatty Acids on
Inflammatory Gene Expression in Healthy Humans." J. Biol. Chem.,
284(23): 15400-15407 (2009) (published online Apr. 9, 2009). cited
by applicant .
Webcast Information for the Oct. 16, 2013 Meeting of the
Endocrinologic and Metabolic Drugs Advisory Committee, (1 page).
cited by applicant .
Weber, P. "Triglyceride-lowering effect of n-3 long chain
polyunsaturated fatty acid: eicosapentaenoic acid vs.
docosahexaenoic acid." Lipids 34: S269 (1999). cited by applicant
.
Wei et al., Effects of [EPA] Versus [DHA] on Serum Lipids: A
Systematic Review and Meta-Analysis, 13 Current Atherosclerosis
Rep. 13(6):474-483 (2011). cited by applicant .
Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate
incomplete failure time data by modeling marginal distributions. J
Am Stat Assoc. 84(408):1065-1073 (publication date Dec. 1989).
cited by applicant .
Westerveld H.T. et al., "Effects of low-dose EPA-Eon glycemic
control, lipid profile, lipoprotein(a), platelet aggretation,
viscosity, and platelet and vessel wall interaction in NIDDM"
Diabetes Care 16(5):683-8 (May 1993). cited by applicant .
Westphal, S., et al., "Postprandial chylomicrons and VLDLs in
severe hypertriacylglycerolemia are lowered more effectively than
are chylomicron remnants after treatment with n23 fatty acids." Am
J Clin Nutr 71:914-20 (2000). cited by applicant .
Whelan, J., et al., "Evidence that dietary arachidonic acid
increases circulating triglycerides." Lipids 30, 425-429 (1995).
cited by applicant .
Wierzbicki, A.S., "Editorial: Newer, lower, better? Lipid drugs and
cardiovascular disease--the continuing story." Int J Clin Pract,
61(7):1064-1067 (2007). cited by applicant .
Wierzbicki, A.S., "Editorial: Raising HDL-C: back to the future?"
Int J Clin Pract, 61(7): 1069-1071 (2007). cited by applicant .
Wikipedia, "Diabetes mellitus," Dec. 12, 2016 (Dec. 12, 2016),
retrieved on Jul. 30, 2018 from
https://en.wikipedia.org/w/index.php?title=Diabetes_mellitus&oldid=754431-
573; entire document, especially p. 1, paragraph 1. cited by
applicant .
Wikipedia, "Ethyl eicosapentaenoic acid," Apr. 1, 2016 (Apr. 1,
2016); retrieved on Jul. 27, 2018 from
https://en.wikipedia.org/w/index.php?title=Ehtyl_eicosapentaenoic_acid&ol-
did=713086755; entire document, especially p. 1, col. 2 and p. 3,
paragraph 2. cited by applicant .
Williams et al., "NADPH Oxidase Inhibitors New Antihypertensive
Agents?" J. Cardiovasc Pharmacol 50(1):9-16 (Jul. 1, 2007). cited
by applicant .
Willumsen, N. et al., Biochimica et Biophysica Acta. vol. 1369, "On
the effect of 2-deuterium- and 2-methyl-eicosapentaenoic acid
derivatives on triglycerides, peroxisomal beta-oxidation and
platelet aggregation in rats," pp. 193-203, (1998). cited by
applicant .
Willumsen, N., et al., "Eicosapentaenoic acid, but not
docosahexaenoic acid, increased, mitochondrial fatty acid oxidation
and upregulates 2,3-dienoyl-CoA reductase gene expression in rats."
Lipids, 31:579-592 (1996). cited by applicant .
Wilson Omega 3 fish oil: EPA versus DHA (Dietivity.com, 1-16)
(2006). cited by applicant .
Wilt, VM & Gumm, JG, "Isolated low high-density lipoprotein
cholesterol", Ann. Pharmacol., 31:89-97, (1997). cited by applicant
.
Wink, J., et al., "Effect of very-low-dose niacin on high-density
lipoprotein in patients undergoing long-term statin therapy", Am.
Heart J., 143:514-518, (2002). cited by applicant .
Wittrup HH, Tybj.ae butted.rg-Hansen A, Nordestgaard BG.
Lipoprotein lipase mutations, plasma lipids and lipoproteins, and
risk of ischemic heart disease: a meta-analysis. Circulation.
1999;99:2901-2907. cited by applicant .
Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet.
1994;344(8925):793-795. cited by applicant .
Wojczynski et al., "High-fat meal effect on LDL, HDL and VLDL
particle size and number in the Genetics of Lipid-Lowering Drugs
and Diet Network (GOLDN): an interventional study," Lipids in
Health and Disease 10:181, pp. 1-11 (Oct. 18, 2011). cited by
applicant .
Wojenski, C.M., et al., "Eicosapentaenoic acid ethyl ester as an
antithrombotic agent: comparison to an extract of fish oil."
Biochimica et Biophysica Acta. 1081:33-38 (1991). cited by
applicant .
Wong, S.H., et al., "Effects of eicosapentaenoic and
docosahexaenoic acids on Apoprotein B mRNA and secretion of very
low density lipoprotein in HepG2 cells." Arterioscler. Thromb.
Vasc. Biol. 9;836-841 (1989). cited by applicant .
Wood et al., "Carbohydrate Restriction Alters Lipoprotein
Metabolism by Modifying VLDL, LDL and HDL Subraction Distribution
and Size in Overweight Men," Journ. of Nutrition, 136(2):384-9
(2006). cited by applicant .
Woodman et al., "Effects of Purified Eicosapentaenoic and
Docosahexaenoic Acids on Glycemic Control, Blood Pressure, and
Serum Lipids in Type 2 Diabetic Patients with Treated
Hypertension", The American Journal of Clinical Nutrition: Official
Journal of the American Society for Clinical Nutrition, Inc.,
76(5):1007-1015 (2002). cited by applicant .
Woodman, R.J., et al., "Effects of purified eicosapentaenoic acid
and docosahexaenoic acid on platelet, fibrinolytic and vascular
function in hypertensive type 2 diabetic patients." Atherosclerosis
166: 85-93 (2003). cited by applicant .
Wu et al., "Diabetic dyslipidemia," Metabolism Clinical and
Experimental, 63:1469-1479 (Dec. 2014)(available online Aug. 29,
2014). cited by applicant .
Wu, W.H., et al., "Effects of docosahexaenoic acid supplementation
on blood lipids, estrogen metabolism, and in vivo oxidative stress
in postmenopausal vegetarian women." Eur J Clin Nutr., 60:386-392
(2006). cited by applicant .
Xiao, Y.F., et al., "Inhibitory effect of n-3 fish oil fatty acids
on cardiac Na+/Ca2+ exchange currents in HEK293t cells."
Biochemical and Biophysical Research Communications 321: 116-123
(2004). cited by applicant .
Xiao, Y-F., et al "Blocking effects of polyunsaturated fatty acids
on Na+ channels of neonatal rat ventricular myocytes." Proc. Natl.
Acad. Sci. 92: 11000-11004 (1995). cited by applicant .
Xiao, Y-F., et al., "Fatty acids suppress voltage-gated Na+
currents in HEK293t cells transfected with the a-subunit of the
human cardiac Na+ channel." Proc. Natl. Acad. Sci. 95: 2680-2685
(1998). cited by applicant .
Xydakis, A M et al., "Combination therapy for combined
dyslipidemia," American Journal of Cardiology, Nov. 20, 2002 US,
vol. 90, No. 10 Suppl. 2, p. 21 K-29K (2002). cited by applicant
.
Yacyshyn BR, Thomson AB. The clinical importance of proton pump
inhibitor pharmacokinetics. Digestion 2002 66 (2): 67-78. cited by
applicant .
Yadav D, Pitchumoni CS. Issues in Hyperlipidemic Pancreatitis. J
Clin Gastroenterol 236(1):54-62, 2003. cited by applicant .
Yagi K. Assay for blood plasma or serum. Methods Enzymol.
1984;105:328-331. cited by applicant .
Yamagishi K, Nettleton J, Folsom A. Plasma fatty acid composition
and incident heart failure in middle-aged adults: The
Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J.2008;
156:965-974. cited by applicant .
Yamakawa K, Shimabukuro M, Higa N, Asahi T, Ohba K, Arasaki O, Higa
M, Oshiro Y, Yoshida H, Higa T, Saito T, Ueda S, Masuzaki H, Sata
M. Eicosapentaenoic Acid Supplementation Changes Fatty Acid
Composition and Corrects Endothelial Dysfunction in Hyperlipidemic
Patients. Cardiol Res Practice. 2012; epub Article ID 754181. cited
by applicant .
Yamamoto, H. et al., Improvement of coronary vasomotion with
Eicosapentaenoic acid does not inhibit acetylcholine-induced
coronary vasospasm in patients with variant angina: Jpn Cir J.
59(9):608-16 (1995). cited by applicant .
Yamamoto, K., et al., "4-Hydroxydocosahexaenoic acid, a potent
Peroxisome Proliferator-Activated Receptor C agonist alleviates the
symptoms of DSS-induced colitis." Biochemical and Biophysical
Research Communications 367: 566-572 (2008). cited by applicant
.
Yamano T, Kubo T, Shiono Y, et al. Impact of eicosapentaenoic acid
treatment on the fibrous cap thickness in patients with coronary
atherosclerotic plaque: an optical coherence tomography study. J
Atheroscler Thromb. 2015;22:52-61. cited by applicant .
Yamashita et al., J. Biochem., vol. 122, No. 1, "Acyl-transferases
and Transaclyases Involved in Fatty Acid Remoding of Phospholipids
and Metabolism of Bioactive Lipids in Mammalian Cells", pp. 1-16
(1997). cited by applicant .
Yamashita, N., et al., "Inhibition of natural killer cell activity
of human lymphocytes by eicosapentaenoic acid." Biochem. Biophys.
Res. Comm. 138(3): 1058-1067 (1986). cited by applicant .
Yamazaki et al., "Changes in fatty acid composition in rat blood
and organs after infusion of eicosapentaenoic acid ethyl ester",
Biochim. Biophys. ACTA, 1128(1):35-43, (1992). cited by applicant
.
Yamazaki, et. al., "Dissolution tests by RDC method for soft
gelatin capsules containing ethyl icosapentate,", Pharm. Tech.
Japan, vol. 15, No. 4, pp. 595-603 Abstract (1999) (with English
abstract). cited by applicant .
Yang, S.P., et al., "Eicosapentaenoic acid attenuates vascular
endothelial growth factor-induced proliferation via inhibiting
Flk-1 receptor expression in bovine carotid artery endothelial
cells." J. Cell. Physio. 176:342-349 (1998). cited by applicant
.
Yano T, Mizuguchi K, Takasugi K, Tanaka Y, Sato M. "Effects of
ethyl all-cis-5,8,11,14,17-icosapentaenoate on low density
lipoprotein in rabbits," Yakugaku Zasshi, 115:843-51 (1995). cited
by applicant .
Yano, T., et al., "Effects of
ethyl-all-cis-5,8,11,14,17-icosapentaenoate (EPA-E), pravastatin
and their combination on serum lipids and intimal thickening of
cuff-sheathed carotid artery in rabbits." Life Sciences,
61(20):2007-2015 (1997). cited by applicant .
Yates RA, Wong J, Seiberling M, et al. The effect of anastrozole on
the single-dose pharmacokinetics and anticoagulant activity of
warfarin in healthy volunteers. Br. J. Clin. Pharmacol. May 2001 51
(5): 429-35. cited by applicant .
Yerram, N.R., et al., "Eicosapentaenoic acid metabolism in brain
microvessel endothelium: effect on prostaglandin formation." J.
Lipid Res.30:1747-1757 (1989). cited by applicant .
Yokoyama et al., "Effects of eicosapentaenoic acid on
cardiovascular events in Japanese patients with
hypercholeterolemia: Rationale, design, and baseline
characteristics of the Japan EPA Lipid Intervention Study (JELIS),"
Amer. Heart Journal 146(4):613-620 (2003). cited by applicant .
Yokoyama et al., "Effects of eicosapentaenoic acid on major
coronary events in hypercholesterolaemic patients (JELIS): a
randomized open-label, blinded endpoint analysis", Lancet, vol.
369, pp. 1090-1098 (2007). cited by applicant .
Yorioka, N, "Lipid-lowering therapy and coagulation/fibrinolysis
parameters in patients on peritoneal dialysis," The International
Journal of Artificial Organs, vol. 23(1):27-32 2000. cited by
applicant .
Yoshimura et al., "Effects of highly purified eicosapentaenoic acid
on plasma beta thromboglobulin level and vascular reactivity to
angiotensin II", Artery, 14(5):295-303 (1987). cited by applicant
.
Zaima, N., et al., "Trans geometric isomers of EPA decrease
LXRa-induced cellular triacylglycerol via suppression of SREBP-1c
and PGC-1.beta.," J. Lipid Res. 47: 2712-2717 (2006). cited by
applicant .
Zalewski et al., Role of Lipoprotein-Associated Phospholipase A2 in
Atherosclerosis: Biology, Epidemiology, and Possible Therapeutic
Target, Arteriosclerosis, Thrombosis, & Vascular Biology
25(5):923-931 (2005). cited by applicant .
Zanarini, et al., "Omega-3 Fatty Acid Treatment of Women with
Borderline Personality Disorder: A Double-Blind, Placebo-Controlled
Pilot Study," Am J Psychiatry, 160:167-169 (2003). cited by
applicant .
Zhan, S. et. al."Meta-analysis of the effects of soy protein
containing isoflavones on the lipid profile," Am. J. Clin. Nutr.
(Feb. 2005), 81, p. 397-408. cited by applicant .
Zhang, M., et al., "Effects of eicosapentaenoic acid on the early
stage of type 2 diabetic nephropathy in KKAy/Ta mice: involvement
of anti-inflammation and antioxidative stress." Metabolism Clinical
and Experimental 55:1590-1598 (2006). cited by applicant .
Zhang, Y.W., et al., "Inhibitory effects of eicosapentaenoic acid
(EPA) on the hypoxia/reoxygenation-induced tyrosine kinase
activation in cultured human umbilical vein endothelial cells."
Prostaglandins, Leukotrienes and Essential FattyAcids 67(4):253-261
(2002). cited by applicant .
Zhang, Y.W., et al., "Pretreatment with eicosapentaenoic acid
prevented hypoxia/reoxygenation-induced abnormality in endothelial
gap junctional intercellular communication through inhibiting the
tyrosine kinase activity." Prostaglandins, Leukotrienes and
Essential Fatty Acids 61(1): 33-40 (1999). cited by applicant .
Zhao et al., "Polyunsaturated Fatty Acids are FXR Ligands and
Differentially Regulate Expression of FXR Targets," DNA and Cell
Biology, 23(8):519-526 (Aug. 25, 2004). cited by applicant .
Zhao, G. et al., "Dietary .alpha.-linolenic acid inhibits
proinflammatory cytokine production by peripheral blood mononuclear
cells in hypercholesterolemic subjects." Am J Clin Nutr 85:385-91
(2007). cited by applicant .
Zhao, G., et al., "Dietary .alpha.-linolenic acid reduces
inflammatory and lipid cardiovascular risk factors in
hypercholesterolemic men and women." J. Nutr. 134: 2991-2997
(2004). cited by applicant .
Zheng et al., "Function of .omega.-3 long chain unsaturated fatty
acid in metabolic syndrome," Chinese Journal of Endocrinology and
Metabolism, vol. 27, No. 9, pp. 787-790 (Sep. 30, 2011)(with
English translation). cited by applicant .
Ziegler, D., et al., "Treatment of symptomatic diabetic
polyneuropathy with the antioxidant .alpha.-lipoic acid: A 7-month
multicenter randomized controlled trial (ALADIN III Study)."
Diabetes Care 22:1296-1301 (1999). cited by applicant .
Zimmerman JJ, Raible DG, Harper DM, et al. Evaluation of a
potential tigecycline-warfarin drug interaction. Pharmacotherapy
Jul. 2008 28 (7): 895-905. cited by applicant .
Zuijdgeest-van Leeuwen, et al., "N-3 Fatty Acids Administered as
Triacylglycerols or as Ethyl Esters Have Different Effects on Serum
Lipid Concentrations in Healthy Subjects," N-3 Fatty Acids, Lipid
Metabolism and Cancer, pp. 89-100 (2000). cited by applicant .
Zuijdgeest-van Leeuwen, S.D., et al., "Incorporation and washout of
orally administered n-3 fatty acid ethyl esters in different plasma
lipid fractions." British Journal of Nutrition 82:481-488 (1999).
cited by applicant .
Zuijdgeest-van Leeuwen, SD, et al., "Eicosapentaenoic acid inhibits
lipolysis in weight-losing cancer patients as well as in healthy
volunteers," Eur J Gastroenterol & Hepatol., 10(12):A67 (1998).
cited by applicant .
Zvyaga T, Chang SY, Chen C, et al. Evaluation of six proton pump
inhibitors as inhibitors of various human cytochromes P450: focus
on cytochrome P450 2C19. Drug Metab. Dispos. Sep. 2012 40 (9):
1698-711. cited by applicant .
Connor et al, "Are Fish Oils Beneficial in the Prevention and
Treatment of Coronary Artery Disease?", Am J Clin Nutr vol. 66, No.
4, Jan. 1, 1997, pp. 1020S-1031S, XP002502041. cited by applicant
.
Ivanova et al., "Small Dense Low-Density Lipoprotein as Biomarker
for Atherosclerotic Diseases," May 9, 2017, Oxidative Medicine and
Cellular Longevity (2017), 10 pp. cited by applicant .
McCabe, John B. "Literature of Resuscitation", Resuscitation,
Elsevier, IE, vol. 19, No. 3 (Jun. 1, 1990), vol. 19, pp. 303-319,
DOI: 10.1016/0300-9572 (90)90109-R. cited by applicant .
Pepys, M.B. et al, "C-reactive protein: a critical update", Journal
of Clinical Investigation, e-pub Jun. 15, 2003; Jul. 2003, vol.
111(12), pp. 1805-1812. cited by applicant .
Siscovick et al., "Dietary Intake and Cell Membrane levels of
Long-chain N-3 Polyunsaturated Fatty Acids and the Risk of Primary
Cardiac Arrest", JAMA, vol. 274, No. 17, Nov. 1, 1995, pp.
1363-1367, XP008041164. cited by applicant .
Thomas II et al., "Prostate Cancer Risk in Men with Baseline
History of Coronary Artery Disease: Results from the REDUCE Study,"
Cancer Epidemiology, Biomarkers and Prevention, 21(4) published
online Feb. 7, 2012. cited by applicant .
Balfour et al., "Rosiglitazone," Drugs, 57(6):921-930 (Jun. 1999).
cited by applicant .
Brinton et al., "Effects of icosapent ethyl on lipid and
inflammatory parameters in patients with diabetes mellitus-2,
residual elevated triglycerides (200-500 mg/dL), and on statin
therapy at LDL-C goal: the ANCHOR study," Cardiovasc. Diabetol.
Jul. 2013 9;12:100. doi: 10.1186/1475-2840-12-100. cited by
applicant .
Daniel et al., "The Effect of Elevated Triglycerides on the Onset
and Progression of Coronary Artery Disease: A Retrospective Chart
Review," Cholesterol, vol. 2015, Article ID 292935, 5 pages (epub
Nov. 4, 2015). cited by applicant .
Hamazaki et al., "Effects of fish oil rich in eicosapentaenoic acid
on serum lipid in hyperlipidemic hemodialysis patients," Kidney
Int'l., 26:81-84 (Jul. 1984). cited by applicant .
Lovaza TM (omega-3-acid ethyl esters) Capsules, Aug. 2007 (Aug. 1,
2007)m oaget 1-2, XP055589332. cited by applicant .
Meyer et al., "Comparison of Seal Oil to Tuna Oil on Plasma Lipid
Levels and Blood Pressure in Hypertiglyceridaemic Subjects,"
Lipids, 44:827-835 (Sep. 2009). cited by applicant .
Nelson et al. "Icosapent Ethyl for Treatment of Elevated
Triglyceide Levels," Annals of Pharmacotheraphy, 47(11):1517-1523
(Nov. 2013/epub Nov. 5, 2013). cited by applicant .
Poirier, "Obesity and Cardiovasculr Disease: Pathophysiology,
Evaluation, and Effect of Weight Loss", Circulation, Feb. 2006
14;113(6):898-918. Epub Dec. 27, 2005. cited by applicant .
Shearer et al., "Red Blood Cell Fatty Acid Patters and Acute
Coronary Syndrome," PLoS One 4(5): e5444, publ. May 6, 2009
(doi:10.1371/journal/pone.0005444). cited by applicant .
Stielow et al., "Novel Nox Inhibitor of oxLDL-Induced Reactive
Oxygen Species Formation in Human Endothelial Cells," Biochem.
Biophys. Res. Comm., 344:200-205 (May 26, 2006/epub Mar. 26, 2006).
cited by applicant .
Third Report of the National Cholesterol Education Program (NCEPP)
Expert Panel on Detection, Evaluation, and Treatment of High blood
Cholesterol in Adults (Adult Treatment PanelIII) May 2001. cited by
applicant .
Thomas et al., "Renal Failure--Measuring the Glomerular Filtration
Rate," Dtsch Arztebl Int., Dec. 18, 2009, 106(51-52); 849-54. cited
by applicant .
Yao et al., "Oxidized high density lipoprotein induces macrophage
apoptosis via toll-like receptor 4-dependent CHOIP pathway," Journ.
Lipid Res., 58:164-177 (Jan. 2017)(First published Nov. 28, 2016).
cited by applicant .
Zimmer et al., "Danger signaling in Atherosclerosis," Circ. Res.,
2015; 116:323-340. cited by applicant.
|
Primary Examiner: Rao; Savitha M
Attorney, Agent or Firm: Perkins Coie LLP
Parent Case Text
PRIORITY CLAIM
This application claims priority to U.S. Provisional Application
No. 62/735,670 filed on Sep. 24, 2018, U.S. Provisional Application
No. 62/735,680 filed on Sep. 24, 2018, U.S. Provisional Application
No. 62/758,387 filed on Nov. 9, 2019, U.S. Provisional Application
No. 62/813,888 filed on Mar. 5, 2019, and U.S. Provisional
Application No. 62/818,514 filed on Mar. 14, 2019, the entire
contents of each of which are incorporated herein by reference and
relied upon.
Claims
The invention claimed is:
1. A method of reducing risk of one or more of: myocardial
infarction, stroke, cardiovascular death, unstable angina, coronary
revascularization procedures and/or hospitalizations for unstable
angina in a subject in need thereof, the method comprising
administering daily to the subject 4 g of eicosapentaenoic acid
ethyl ester (E-EPA) and a high intensity statin regimen, wherein
the subject has elevated triglyceride levels and (1) established
cardiovascular disease, or (2) diabetes and at least 2 additional
risk factors for cardiovascular disease, wherein the high intensity
statin regimen comprises about 40 mg to about 80 mg per day of
atorvastatin or about 20 mg to about 40 mg per day of
rosuvastatin.
2. The method of claim 1, wherein risk of occurrence of one or more
components of a 3-point composite endpoint composed of
cardiovascular death, non-fatal myocardial infarction, or non-fatal
stroke is reduced in the subject.
3. The method of claim 2, wherein risk of occurrence of one or more
components of the 3-point composite endpoint composed of
cardiovascular death, non-fatal myocardial infarction, or non-fatal
stroke is reduced by at least about 20% in the subject.
4. The method of claim 1, wherein risk of occurrence of one or more
components of a 5-point composite endpoint composed of
cardiovascular death, non-fatal stroke, non-fatal myocardial
infarction, coronary revascularization, or unstable angina
requiring hospitalization is reduced in the subject.
5. The method of claim 4, wherein risk of occurrence of one or more
components of the 5-point composite endpoint composed of
cardiovascular death, non-fatal myocardial infarction, non-fatal
stroke, coronary revascularization, or unstable angina requiring
hospitalization is reduced by at least about 20% in the
subject.
6. The method of claim 1, wherein the subject is less than about 65
years of age.
7. The method of claim 1, wherein the subject has a high
sensitivity reactive protein (hsCRP) level of 2 mg/L or less.
8. The method of claim 1, wherein the subject has a fasting
baseline triglyceride level of at least about 200 mg/dL and a
fasting baseline high density lipoprotein-C (HDL-C) level of about
35 mg/dL or less.
9. The method of claim 1, wherein the subject has a fasting
baseline triglyceride level of about 135 mg/dL to about 500
mg/dL.
10. The method of claim 1, wherein the administering occurs for at
least about 2 years.
Description
BACKGROUND
Cardiovascular disease is one of the leading causes of death in the
United States and most European countries. It is estimated that
over 70 million people in the United States alone suffer from a
cardiovascular disease or disorder including but not limited to
high blood pressure, coronary heart disease, dyslipidemia,
congestive heart failure and stroke.
Lovaza.RTM., a lipid regulating agent, is indicated as an adjunct
to diet to reduce triglyceride levels in adult patients with very
high triglyceride levels. Unfortunately, Lovaza.RTM. can
significantly increase LDL-C and/or non-HDL-C levels in some
patients. A need exists for improved treatments for cardiovascular
diseases and disorders.
SUMMARY
In various embodiments, the present disclosure provides methods of
treating and preventing cardiovascular diseases and disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic of the study design according to an
embodiment of the present disclosure.
FIG. 2 is a schematic showing disposition of patients according to
an embodiment of the present disclosure.
FIGS. 3A and 3B are representative Kaplan-Meier event curves for
the cumulative incidence of the primary composite endpoints. FIGS.
3A and 3B indicate a 25% relative risk reduction for the primary
composite endpoint over the course of 5 years.
FIG. 4 is a representative forest plot of individual components of
primary endpoints analyzed as time to first event of each
individual endpoint and indicates that each component,
individually, was reduced.
FIGS. 5A and 5B are representative Kaplan-Meier event curves for
the cumulative incidence of the key secondary composite endpoints.
FIGS. 5A and 5B indicate that there was a 26% RRR for the key
secondary composite endpoint over the course of 5 years.
FIGS. 6 and 7 are representative forest plots of primary efficacy
outcomes in select prespecified subgroups. FIGS. 6 and 7 indicate
that a subject's baseline triglyceride levels (e.g., 150 vs.
<150 mg/dL or .gtoreq.200 or <200 mg/dL) did not influence
the primary endpoint outcomes.
FIGS. 8 and 9 are representative forest plots of secondary efficacy
outcomes in select prespecified subgroups. FIGS. 8 and 9 indicate
that a subject's baseline triglyceride levels (e.g., .gtoreq.150
vs. <150 mg/dL or 200 or <200 mg/dL) did not influence the
key secondary endpoint outcomes.
FIGS. 10A and 10B are representative Kaplan-Meier curves of primary
and key secondary endpoints by achieved triglyceride level at 1
year. FIGS. 10A and 10B indicate that patient's triglyceride levels
had no influence on the efficacy of icosapent ethyl as compared
with placebo with respect to the primary or key secondary efficacy
endpoint outcomes.
FIG. 11 is a representative forest plot of prespecified
hierarchical testing of endpoints and indicates that all individual
and composite ischemic endpoints were significantly reduced by
icosapent ethyl (AMR101).
FIG. 12 is a schematic of the study design according to an
embodiment of the present disclosure.
FIG. 13 is a representative bar graph depicting the distribution of
first, second, and recurrent ischemic events in patients. FIG. 13
indicates that the first, second, and recurrent ischemic events
were reduced in patients randomized to icosapent ethyl (IPE)
compared to placebo.
FIG. 14 is a representative overall cumulative event Kaplan-Meier
event curve for the primary endpoint indicating that overall
cumulative primary endpoints were reduced in patients randomized to
icosapent ethyl.
FIG. 15 is a representative cumulative event Kaplan-Meier event
curve for the primary endpoint for patients in the secondary
prevention cohort, which, similar to FIG. 14, indicates that
cumulative primary endpoints were also reduced in patients in the
secondary prevention cohort randomized to icosapent ethyl.
FIG. 16 is a representative cumulative event Kaplan-Meier event
curve for the primary endpoint for patients in the primary
prevention cohort, which, similar to FIGS. 14 and 15, indicates
that cumulative primary endpoints were also reduced in patients in
the primary prevention cohort randomized to icosapent ethyl.
FIG. 17 is a representative forest plot of the total event for each
occurrence of the primary endpoint. FIG. 17 indicates that the
times to first, second, third, or fourth occurrences of the primary
composite endpoint were consistently reduced in the icosapent ethyl
group as compared to placebo.
FIG. 18 includes representative pie charts for the proportion of
first and subsequent primary endpoint events, overall and by
component.
FIG. 19 is a representative graph depicting the risk difference in
100 patients treated for five years with icosapent ethyl versus
placebo of the composite primary endpoint.
FIG. 20 is a representative forest plot of the total event for each
occurrence of the primary and key secondary efficacy endpoints.
FIG. 20 indicates that the total events for each component of the
primary endpoint events were significantly reduced.
FIG. 21 is a representative overall cumulative event Kaplan-Meier
curve for the key secondary endpoint indicating that overall
cumulative key secondary endpoints were reduced in patients
randomized to icosapent ethyl.
FIG. 22 is a representative cumulative event Kaplan-Meier curve for
the key secondary endpoint for patients in the secondary prevention
cohort, which similar to FIG. 21 indicates that cumulative key
secondary endpoints were also reduced in patients in the secondary
prevention cohort randomized to icosapent ethyl.
FIG. 23 is representative cumulative event Kaplan-Meier curve for
the key secondary endpoint for patients in the primary prevention
cohort, which, similar to FIGS. 21 and 22, indicates that
cumulative primary endpoints were also reduced in patients in the
primary prevention cohort randomized to icosapent ethyl.
FIG. 24 is a representative overall cumulative Kaplan-Meier event
curve as a function of years since randomization for the primary
endpoint indicating that overall cumulative primary endpoints were
reduced in patients randomized to icosapent ethyl.
FIG. 25 is a representative overall cumulative event Kaplan-Meier
curve as a function of years since randomization for the key
secondary endpoint indicating that overall cumulative key secondary
endpoints were reduced in patients randomized to icosapent
ethyl.
FIG. 26 is a representative Kaplan-Meier curve for recurrent events
as a function of years since randomization of the primary endpoint
for patients in the secondary prevention cohort indicating that
cumulative primary endpoints were reduced in patients in the
secondary prevention cohort randomized to icosapent ethyl.
FIG. 27 is a representative Kaplan-Meier curve as a function of
years since randomization for recurrent events of the key secondary
endpoint for patients in the secondary prevention cohort indicating
that cumulative key secondary endpoints were also reduced in
patients in the secondary prevention cohort randomized to icosapent
ethyl.
FIG. 28 is a representative Kaplan-Meier curve as a function of
years since randomization for recurrent events of the primary
endpoint for patients in the primary prevention cohort indicating
that cumulative primary endpoints were also reduced in patients in
the primary prevention cohort randomized to icosapent ethyl.
FIG. 29 is a representative Kaplan-Meier curve as a function of
years since randomization for recurrent events of the key secondary
endpoint for patients in the primary prevention cohort indicating
that cumulative key secondary endpoints were reduced in patients in
the primary prevention cohort randomized to icosapent ethyl.
FIG. 30 are representative plots of the total events by number of
events per patient for the primary composite endpoints and for each
individual component for patients randomized to icosapent ethyl and
placebo.
FIGS. 31A and 31B are representative flow charts of the total
primary and secondary composite endpoint events for patients
randomized to AMR101 and placebo, respectively.
FIG. 32 includes representative pie charts for a proportion of
first and subsequent primary endpoint events, overall and by
component.
FIG. 33 is a representative bar graph depicting a distribution of
total (i.e., first and subsequent) primary composite endpoint
events in patients. FIG. 33 indicates that there was a 30% relative
risk reduction in total events for the primary composition endpoint
in patients randomized to icosapent ethyl.
FIGS. 34A and 34B are representative Kaplan-Meier curves over time
for total (i.e., first and subsequent) and time to first primary
composite events and secondary composite endpoint events,
respectively. FIGS. 34A and 34B indicate that both primary and key
secondary endpoints were significantly reduced in patients
randomized to icosapent ethyl compare to placebo.
FIG. 35 is a representative forest plot of total primary and key
secondary composite endpoint events and indicates that times to
first, second, and third occurrence of the primary and secondary
endpoints were significantly reduced in patients randomized to
icosapent ethyl compared placebo.
FIG. 36 is a representative forest plot of total primary and key
secondary composite endpoints and each individual component or
endpoint for patients randomized to icosapent ethyl and placebo
indicating that not only was there a significant reduction in the
composite of the primary and key secondary endpoints, but also,
each individual component was also significantly reduced.
FIGS. 37A and 37B are representative forest plots of total primary
and secondary composite endpoints in selected subgroups by the
negative binomial model, respectively, for patients randomized to
icosapent ethyl and placebo.
FIG. 38 is a representative graph depicting the risk difference in
patients treated for five years with icosapent ethyl versus placebo
for total components of the composite primary endpoint and
indicates that approximately 159 total primary endpoint events
could be prevented within that time frame to include 12
cardiovascular deaths, 42 myocardial infarctions, 14 strokes, 76
coronary revascularizations, and 16 episodes of hospitalization for
unstable angina.
FIGS. 39 and 40 show the forest plot for total primary and key
secondary composite endpoint events and first second, and third
occurrences for the reduced dataset with unadjusted and adjusted
values, respectively.
FIGS. 41 and 42 show the forest plots for the total primary
composite endpoint events and total key secondary composite
endpoint events and first, second, and third occurrences for the
reduced data with unadjusted values, respectively.
FIGS. 43 and 44 show the total primary composite endpoint events
and key secondary composite endpoint events and first, second, and
third occurrences for the reduced data set with adjusted values,
respectively.
FIGS. 45 and 46 show the total primary and key secondary composite
endpoint events and first, second, and third occurrences for the
full data set for the unadjusted and adjusted values,
respectively.
FIG. 47 is a representative forest plot depicting the reduction of
total primary composite endpoint events in subjects as a function
of triglyceride level. FIG. 47 indicates that total primary
composite endpoints were reduced in all patients across the entire
triglyceride range and within each of the defined triglyceride
tertiles.
FIG. 48 is a representative forest plot depicting time to first
event of primary composite endpoint events in subjects as a
function of triglyceride level. FIG. 48 demonstrates that the time
to first event of the primary composite endpoint was reduced across
the entire triglyceride range.
FIG. 49 is a representative bar graph for a placebo-corrected
reduction in blood pressure in patients administered icosapent
ethyl 4 g per day.
FIG. 50 is a representative bar graph for the study drug adherence
overtime for each of the first, second, third, and fourth
events.
DETAILED DESCRIPTION
While the present disclosure is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention and is not
intended to limit the invention to the specific embodiments
illustrated. Headings are provided for convenience only and are not
to be construed to limit the invention in any manner. Embodiments
illustrated under any heading may be combined with embodiments
illustrated under any other heading.
The use of numerical values in the various quantitative values
specified in this application, unless expressly indicated
otherwise, are stated as approximations as though the minimum and
maximum values within the stated ranges were both preceded by the
word "about." It is to be understood, although not always
explicitly stated, that all numerical designations are preceded by
the term "about." It is to be understood that such range format is
used for convenience and brevity and should be understood flexibly
to include numerical values explicitly specified as limits of a
range, but also to include all individual numerical values or
sub-ranges encompassed within that range as if each numerical value
and sub-range is explicitly specified. For example, a ratio in the
range of about 1 to about 200 should be understood to include the
explicitly recited limits of about 1 and about 200, but also to
include individual ratios such as about 2, about 3, and about 4,
and sub-ranges such as about 10 to about 50, about 20 to about 100,
and so forth. It also is to be understood, although not always
explicitly stated, that the reagents described herein are merely
exemplary and that equivalents of such are known in the art.
The term "about," as used herein when referring to a measurable
value such as an amount or concentration and the like, is meant to
encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the
specified amount.
The term "derivative," as used herein when referring to a fatty
acid, is meant to encompass any modified form of the fatty acid
that was derived for example, by a chemical reaction from the fatty
acid in free acid form (i.e., terminal carboxylic acid functional
group). Non-limiting examples of fatty acid derivatives as used
herein include alkyl esters such as methyl esters, propyl esters,
butyl esters, or ethyl esters, a salt of the fatty acid such as a
lithium, sodium, or potassium salt, or glyceride form of the fatty
acid such as a mono-, di-, or triglyceride fatty acid.
In one embodiment, the free fatty acid of eicosapentaenoic acid is
administered to the subject and the amount administered is the gram
weight sufficient to substantially match the pharmacokinetic
profile produced by administration of 4 g of E-EPA per day to a
human subject. In another embodiment, a derivative of
eicosapentaenoic acid is administered to the subject and the amount
administered is the gram weight sufficient to substantially match
the pharmacokinetic profile produced by administration of 4 g of
E-EPA per day to a human subject. With respect to a dose of 3.7 g
per day of eicosapentaenoic acid, a dose-equivalent amount of E-EPA
is about 4 g of E-EPA per day.
The phrase "control subject," as used herein refers to any subject
used as a basis for comparison to the test subject. A control
subject includes, but is not limited to, any subject who has not
been administered the composition, administered a composition other
than the test composition (e.g., Lovaza.RTM. comprised of 365 mg of
E-EPA and 375 mg of E-DHA), or administered a placebo.
The phrase "cardiovascular risk category 1," as used herein refers
to subjects categorized as having an established cardiovascular
disease. Patients from cardiovascular risk category 1 were
stratified to the secondary prevention cohort. The designations for
patients defined by cardiovascular risk category 1 are collectively
referred to as: secondary prevention stratum, secondary prevention
cohort, and the primary risk category.
The phrase "cardiovascular risk category 2," as used herein refers
to a subject categorized as having diabetes (which itself is a risk
factor for cardiovascular disease) and at least one additional risk
factor for cardiovascular disease but who does not have an
established cardiovascular disease. Patients from cardiovascular
risk category 2 were stratified to the primary prevention cohort.
The designations for patients defined by cardiovascular risk
category 1 are collectively referred to as: primary prevention
stratum, primary prevention cohort, and secondary risk
category.
Also, the disclosure of ranges is intended as a continuous range
including every value between the minimum and maximum values
recited as well as any ranges that can be formed by such values.
Also disclosed herein are any and all ratios (and ranges of any
such ratios) that can be formed by dividing a disclosed numeric
value into any other disclosed numeric value. Accordingly, the
skilled person will appreciate that many such ratios, ranges, and
ranges of ratios can be unambiguously derived from the numerical
values presented herein and in all instances such ratios, ranges,
and ranges of ratios represent various embodiments of the present
disclosure.
The phrase "statistical significance," as used herein refers to a
result from data generated by testing or experimentation is not
likely to occur randomly or by chance, but is instead likely to be
attributable to a specific cause. Statistical significance is
evaluated from a calculated probability (p-value), where the
p-value is a function of the means and standard deviations of the
data samples and indicates the probability under which a
statistical result occurred by chance or by sampling error. A
result is considered statistically significant if the p-value is
0.05 or less, corresponding to a confidence level of 95%.
Comprising" or "comprises" is intended to mean that the
compositions and methods include the recited elements, but not
excluding others. "Consisting essentially of" when used to define
compositions and methods, shall mean excluding other elements of
any essential significance to the combination for the stated
purpose. Thus, a composition consisting essentially of the elements
as defined herein would not exclude other materials or steps that
do not materially affect the basic and novel characteristic(s) of
the claimed invention. "Consisting of" shall mean excluding more
than trace elements of other ingredients and substantial method
steps. Embodiments defined by each of these transition terms are
within the scope of this invention.
List of abbreviations: ANOVA, analysis of variance; ASCVD,
atherosclerotic cardiovascular disease; CI, confidence interval;
RRR, relative risk reduction; HR, hazard ratio; CV, cardiovascular;
DM, diabetes mellitus; HDL-C, high-density lipoprotein cholesterol;
HIV/AIDS, human immunodeficiency virus/acquired immune deficiency
syndrome; ICD-9, International Classification of Diseases, Ninth
Revision; TG, triglyceride; TC, total cholesterol; VLDL-C very low
dense lipoprotein cholesterol, apo B, apolipoprotein B; hsCRP, high
sensitivity-C reactive protein; hsTnT, high-sensitivity troponin;
RLP-C, remnant like particle cholesterol; LDL-C, low-density
lipoprotein cholesterol; MI, myocardial infarction; non-HDL-C,
non-high density lipoprotein cholesterol; PAD, peripheral artery
disease; REDUCE-IT, Reduction of Cardiovascular Events with
Icosapent Ethyl-Intervention Trial; SD, standard deviation; TG,
triglycerides; and HLB; hydrophilic lipophilic balance.
Compositions
In one embodiment, a composition of the disclosure is administered
to a subject in an amount sufficient to provide a daily dose of
eicosapentaenoic acid of about 1 mg to about 10,000 mg, 25 about
5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg,
or about 100 mg to about 1000 mg, for example about 75 mg, about
100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,
about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325
mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about
450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg,
about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675
mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about
800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg,
about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025
mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg,
about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about
1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350
mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg,
about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about
1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675
mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg,
about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about
1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000
mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg,
about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about
2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325
mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg,
about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about
2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650
mg, about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg,
about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg, about
2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975
mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg,
about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about
3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300
mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg,
about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about
3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625
mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg,
about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about
3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950
mg, about 3975 mg, about 4000 mg, about 4025 mg, about 4050 mg,
about 4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about
4175 mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275
mg, about 4300 mg, about 4325 mg, about 4350 mg, about 4375 mg,
about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about
4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600
mg, about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg,
about 4725 mg, about 4750 mg, about 4775 mg, about 4800 mg, about
4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about 4925
mg, about 4950 mg, about 4975 mg, about 5000 mg, about 5025 mg,
about 5050 mg, about 5075 mg, about 5100 mg, about 5125 mg, about
5150 mg, about 5175 mg, about 5200 mg, about 5225 mg, about 5250
mg, about 5275 mg, about 5300 mg, about 5325 mg, about 5350 mg,
about 5375 mg, about 5400 mg, about 5425 mg, about 5450 mg, about
5475 mg, about 5500 mg, about 5525 mg, about 5550 mg, about 5575
mg, about 5600 mg, about 5625 mg, about 5650 mg, about 5675 mg,
about 5700 mg, about 5725 mg, about 5750 mg, about 5775 mg, about
5800 mg, about 5825 mg, about 5850 mg, about 5875 mg, about 5900
mg, about 5925 mg, about 5950 mg, about 5975 mg, about 6000 mg,
about 6025 mg, about 6050 mg, about 6075 mg, about 6100 mg, about
6125 mg, about 6150 mg, about 6175 mg, about 6200 mg, about 6225
mg, about 6250 mg, about 6275 mg, about 6300 mg, about 6325 mg,
about 6350 mg, about 6375 mg, about 6400 mg, about 6425 mg, about
6450 mg, about 6475 mg, about 6500 mg, about 6525 mg, about 6550
mg, about 6575 mg, about 6600 mg, about 6625 mg, about 6650 mg,
about 6675 mg, about 6700 mg, about 6725 mg, about 6750 mg, about
6775 mg, about 6800 mg, about 6825 mg, about 6850 mg, about 6875
mg, about 6900 mg, about 6925 mg, about 6950 mg, about 6975 mg,
about 7000 mg, about 7025 mg, about 7050 mg, about 7075 mg, about
7100 mg, about 7125 mg, about 7150 mg, about 7175 mg, about 7200
mg, about 7225 mg, about 7250 mg, about 7275 mg, about 7300 mg,
about 7325 mg, about 7350 mg, about 7375 mg, about 7400 mg, about
7425 mg, about 7450 mg, about 7475 mg, about 7500 mg, about 7525
mg, about 7550 mg, about 7575 mg, about 7600 mg, about 7625 mg,
about 7650 mg, about 7675 mg, about 7700 mg, about 7725 mg, about
7750 mg, about 7775 mg, about 7800 mg, about 7825 mg, about 7850
mg, about 7875 mg, about 7900 mg, about 7925 mg, about 7950 mg,
about 7975 mg, about 8000 mg, about 8025 mg, about 8050 mg, about
8075 mg, about 8100 mg, about 8125 mg, about 8150 mg, about 8175
mg, about 8200 mg, about 8225 mg, about 8250 mg, about 8275 mg,
about 8300 mg, about 8325 mg, about 8350 mg, about 8375 mg, about
8400 mg, about 8425 mg, about 8450 mg, about 8475 mg, about 8500
mg, about 8525 mg, about 8550 mg, about 8575 mg, about 8600 mg,
about 8625 mg, about 8650 mg, about 8675 mg, about 8700 mg, about
8725 mg, about 8750 mg, about 8775 mg, about 8800 mg, about 8825
mg, about 8850 mg, about 8875 mg, about 8900 mg, about 8925 mg,
about 8950 mg, about 8975 mg, about 9000 mg, about 9025 mg, about
9050 mg, about 9075 mg, about 9100 mg, about 9125 mg, about 9150
mg, about 9175 mg, about 9200 mg, about 9225 mg, about 9250 mg,
about 9275 mg, about 9300 mg, about 9325 mg, about 9350 mg, about
9375 mg, about 9400 mg, about 9425 mg, about 9450 mg, about 9475
mg, about 9500 mg, about 9525 mg, about 9550 mg, about 9575 mg,
about 9600 mg, about 9625 mg, about 9650 mg, about 9675 mg, about
9700 mg, about 9725 mg, about 9750 mg, about 9775 mg, about 9800
mg, about 9825 mg, about 9850 mg, about 9875 mg, about 9900 mg,
about 9925 mg, about 9950 mg, about 9975 mg, or about 10,000
mg.
In one embodiment, a composition for use in methods of the
disclosure comprises eicosapentaenoic acid, or a pharmaceutically
acceptable ester, derivative, conjugate or salt thereof, or
mixtures of any of the foregoing, collectively referred to herein
as "EPA." The term "pharmaceutically acceptable" in the present
context means that the substance in question does not produce
unacceptable toxicity to the subject or interaction with other
components of the composition. In one embodiment, derivatives of
EPA include, but are not limited to, methyl or other alkyl esters,
re-esterified monoglycerides, re-esterified diglycerides and
re-esterified triglycerides or mixtures thereof. In one embodiment,
such derivatives of EPA are administered daily in amounts
containing the same number of moles of EPA contained in 4 grams of
ethyl icosapentate.
In another embodiment, the EPA comprises an eicosapentaenoic acid
ester. In another embodiment, the EPA comprises a C.sub.1-C.sub.5
alkyl ester of eicosapentaenoic acid. In another embodiment, the
EPA comprises eicosapentaenoic acid ethyl ester (E-EPA),
eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl
ester, or eicosapentaenoic acid butyl ester.
In another embodiment, the EPA is in the form of ethyl-EPA,
methyl-EPA, lithium EPA, mono-, di- or triglyceride EPA or any
other ester or salt of EPA, or the free acid form of EPA. The EPA
may also be in the form of a 2-substituted derivative or other
derivative which slows down its rate of oxidation but does not
otherwise change its biological action to any substantial degree.
Where any particular form of EPA (e.g. eicosapentaenoic acid ethyl
ester, icosapent ethyl or E-EPA) is referred to throughout this
application, any pharmaceutically acceptable derivative of EPA can
be substituted in its place including icosapent methyl or
eicosapentaenoic acid in free acid form. Eicosapentaenoic acid
ethyl ester, icosapent ethyl, and E-EPA are referenced
interchangeably.
In another embodiment, EPA is present in a composition useful in
accordance with methods of the disclosure in an amount of about 50
mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg
to about 1000 mg, for example about 75 mg, about 100 mg, about 125
mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about
250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg,
about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475
mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about
600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg,
about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825
mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about
950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg,
about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about
1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275
mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg,
about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about
1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600
mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg,
about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about
1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925
mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg,
about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about
2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250
mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg,
about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about
2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575
mg, about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg,
about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about
2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900
mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg,
about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about
3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225
mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg,
about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about
3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550
mg, about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg,
about 3675 mg, about 3700 mg, about 3725 mg, about 3750 mg, about
3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about 3875
mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg,
about 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg, about
4100 mg, about 4125 mg, about 4150 mg, about 4175 mg, about 4200
mg, about 4225 mg, about 4250 mg, about 4275 mg, about 4300 mg,
about 4325 mg, about 4350 mg, about 4375 mg, about 4400 mg, about
4425 mg, about 4450 mg, about 4475 mg, about 4500 mg, about 4525
mg, about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg,
about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about
4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850
mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg,
about 4975 mg, or about 5000 mg.
In another embodiment, a composition useful in accordance with the
disclosure contains not more than about 10%, not more than about
9%, not more than about 8%, not more than about 7%, not more than
about 6%, not more than about 5%, not more than about 4%, not more
than about 3%, not more than about 2%, not more than about 1%, or
not more than about 0.5%, by weight, docosahexaenoic acid (DHA), if
any. In another embodiment, a composition of the disclosure
contains substantially no DHA. In still another embodiment, a
composition useful in the present disclosure contains no DHA and/or
derivative thereof. In one embodiment, derivatives of DHA include,
but are not limited to, methyl or other alkyl esters, re-esterified
monoglycerides, re-esterified diglycerides and re-esterified
triglycerides or mixtures thereof.
In another embodiment, EPA comprises at least about 70%, at least
about 80%, at least about 90%, at least about 95%, at least about
96%, at least about 97%, at least about 98%, at least about 99%, or
1 about 100%, by weight, of all fatty acids present in a
composition that is useful in methods of the present
disclosure.
In some embodiments, the composition comprises at least 96% by
weight of eicosapentaenoic acid ethyl ester and less than about 2%
by weight of a preservative. In some embodiments, the preservative
is a tocopherol such as all-racemic .alpha.-tocopherol.
In another embodiment, a composition useful in accordance with
methods of the disclosure contains less than about 10%, less than
about 9%, less than about 8%, less than about 7%, less than about
6%, less than about 5%, less than about 4%, less than about 3%,
less than about 2%, less than about 1%, less than about 0.5% or
less than about 0.25%, by weight of the total composition or by
weight of the total fatty acid content, of any fatty acid other
than EPA. Illustrative examples of a "fatty acid other than EPA"
include linolenic acid (LA), arachidonic acid (AA), docosahexaenoic
acid (DHA), alpha-linolenic acid (ALA), stearadonic acid (STA),
eicosatrienoic acid (ETA) and/or docosapentaenoic acid (DPA). In
another embodiment, a composition useful in accordance with methods
of the disclosure contains about 0.1% to about 4%, about 0.5% to
about 3%, or about 1% to about 2%, by weight, of total fatty acids
other than EPA and/or DHA. In one embodiment, fatty acids other
than EPA include derivatives of those fatty acids. Derivatives of
the fatty acids include, but are not limited to, methyl or other
alkyl esters, re-esterified monoglycerides, re-esterified
diglycerides and re-esterified triglycerides or mixtures thereof of
the fatty acids.
In another embodiment, a composition useful in accordance with the
disclosure has one or more of the following features: (a)
eicosapentaenoic acid ethyl ester represents at least about 96%, at
least about 97%, or at least about 98%, by weight, of all fatty
acids present in the composition; (b) the composition contains not
more than about 4%, not more than about 3%, or not more than about
2%, by weight, of total fatty acids other than eicosapentaenoic
acid ethyl ester; (c) the composition contains not more than about
0.6%, not more than about 0.5%, or not more than about 0.4% of any
individual fatty acid other than eicosapentaenoic acid ethyl ester;
(d) the composition has a refractive index (20.degree. C.) of about
1 to about 2, about 1.2 to about 1.8 or about 1.4 to about 1.5; (e)
the composition has a specific gravity (20.degree. C.) of about 0.8
to about 1.0, about 0.85 to about 0.95 or about 0.9 to about 0.92;
(e) the composition contains not more than about 20 ppm, not more
than about 15 ppm or not more than about 10 ppm heavy metals, (f)
the composition contains not more than about 5 ppm, not more than
about 4 ppm, not more than about 3 ppm, or not more than about 2
ppm arsenic, and/or (g) the composition has a peroxide value of not
more than about 5 meq/kg, not more than about 4 meq/kg, not more
than about 3 meq/kg, or not more than about 2 meq/kg.
In some embodiments, a composition for use in accordance with the
disclosure is a self-emulsifying composition. In some embodiments,
the self-emulsifying composition comprises at least one compound
selected from the group consisting of an omega-3 fatty acid and
derivative thereof (e.g., pharmaceutically acceptable salt and/or
ester). In another embodiment, the composition comprises an
emulsifier. In some embodiments, the emulsifier has a hydrophilic
lipophilic balance (HLB) of at least about 10. Non-limiting
examples of emulsifiers include polyoxyethylene hydrogenated castor
oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene
castor oil, polyethylene glycol fatty acid ester, polyoxyethylene
polyoxypropylene glycol, sucrose fatty acid ester, and lecithin. In
another embodiment, the omega-3 fatty acids or derivative thereof
are present in an amount of about 50% to about 95% by weight of the
total weight of the composition or by weight of the total fatty
acids of the total composition. In some embodiments, the omega-3
fatty acid is EPA and/or DHA. In some embodiments, the EPA is
present in amount at least about 95%, by weight, of all fatty acids
present in the self-emulsifying composition. In another embodiment,
the composition contains substantially no DHA. In yet another
embodiment, the composition contains substantially no ethanol.
In another embodiment, the composition is a self-emulsifying
composition comprising about 50% to about 95% by weight of the
total weight of the composition at least one compound selected from
the group consisting of omega-3 polyunsaturated fatty acids and
derivative thereof (e.g., pharmaceutically acceptable salt and/or
ester). In another embodiment, the composition comprises about 1%
to about 20% by weight of the total weight of the composition, a
sucrose fatty acid ester as an emulsifier having a hydrophilic
lipophilic balance of at least about 10. In another embodiment, the
composition comprises glycerin. In another embodiment, the
composition comprises about 0% to about 5% by weight of the total
composition, ethanol. In another embodiment, the self-emulsifying
composition comprises about 50% to about 95% by weight of the total
weight of the composition, at least one compound selected from the
group consisting of omega-3 polyunsaturated fatty acids and
derivative thereof; about 1% to about 20%, by weight of the total
weight of the composition, a sucrose fatty acid ester as an
emulsifier having a HLB of at least about 10; glycerin; and about
0% to about 4% by weight of the total weight of the composition,
ethanol. In another embodiment, the sucrose fatty acid ester is one
or more of: sucrose laurate, sucrose myristate, sucrose palmitate,
sucrose stearate, or sucrose oleate. In another embodiment, the
omega-3 polyunsaturated fatty acid is one or more of EPA, DHA, or
derivative thereof. In yet another embodiment, the omega-3
polyunsaturated fatty acid is ethyl-EPA and/or ethyl-DHA.
In another embodiment, the composition is a self-emulsifying
composition comprising about 50% to about 95% by weight of the
total weight of the composition, at least one compound selected
from the group consisting of omega-3 polyunsaturated fatty acids
and derivative thereof (e.g., pharmaceutically acceptable salt and
ester); and about 5% to about 50%, by weight, of the total weight
of the composition an emulsifier having a HLB of at least about 10;
wherein ethanol content is up to about 4% by weight of the total
weight of the composition. In some embodiments, the omega-3
polyunsaturated fatty acid is EPA and/or DHA. In another
embodiment, the composition does not contain ethanol. In another
embodiment, the emulsifier is at least one member selected from the
group consisting of polyoxyethylene hydrogenated castor oil,
polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor
oil, polyethylene glycol fatty acid ester, polyoxyethylene
polyoxypropylene glycol, sucrose fatty acid ester, and lecithin. In
another embodiment, the emulsifier is at least one member selected
from the group consisting of polyoxyethylene hydrogenated castor
oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene
castor oil, and sucrose fatty acid ester.
In another embodiment, the hydrogenated castor oil is at least one
member selected from the group consisting of include
polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40)
hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor
oil, polyoxyethylene (60) hydrogenated castor oil, or
polyoxyethylene (100) hydrogenated castor oil. In another
embodiment, the polyoxyethylene sorbitan fatty acid ester is at
least one member selected from the group consisting of
polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan
tristearate, polyoxyethylene sorbitan monostearate, polyoxyethylene
sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate.
In another embodiment, the sucrose fatty acid ester is at least one
member selected from the group consisting of sucrose laurate,
sucrose myristate, sucrose palmitate, sucrose stearate, and sucrose
oleate.
In some embodiments, the composition contains a lecithin selected
from the group consisting of soybean lecithin, enzymatically
decomposed soybean lecithin, hydrogenated soybean lecithin, and egg
yolk lecithin. In another embodiment, the composition contains a
polyhydric alcohol, wherein the polyhydric alcohol is propylene
glycol or glycerin. In another embodiment, the composition contains
at least one member selected from the group consisting of EPA, DHA,
and/or derivative thereof (e.g., their pharmaceutically acceptable
salt and ester), wherein the composition contains ethyl-EPA and/or
ethyl-DHA. In another embodiment, the composition comprises an
emulsifier having a HLB of at least about 10 and is about 10 to
about 100 parts by weight in relation to 100 parts by weight of the
at least one compound selected from the group consisting of omega-3
polyunsaturated fatty acids and/or derivative thereof (e.g.,
pharmaceutically acceptable salt and/or ester).
In another embodiment, the self-emulsifying composition comprises
about 70% to about 90%, by weight, eicosapentaenoic acid ethyl
ester as a first medicinal component. In some embodiments, the
composition further comprises about 0.5 to about 0.6%, by weight,
water. In some embodiments, the composition comprises about 1% to
about 29%, by weight, polyoxyethylene sorbitan fatty acid ester as
an emulsifier. In another embodiment, the composition comprises
about 1 to about 25 parts, by weight, lecithin in relation to about
100 parts, by weight, eicosapentaenoic acid ethyl ester. In yet
another embodiment, the composition comprises pitavastatin,
rosuvastatin, or a salt thereof as a second medicinal component. In
another embodiment, ethanol and/or polyhydric alcohol constitutes
up to about 4% by weight of the total weight of the composition. In
another embodiment, the composition comprises about 0.01 to about 1
part, by weight, of pitavastatin or its salt in relation to about
100 parts, by weight, of the eicosapentaenoic acid ethyl ester, or
about 0.03 to about 5 parts, by weight, rosuvastatin or its salt in
relation to about 100 parts, by weight, eicosapentaenoic acid ethyl
ester as a second medicinal component. In some embodiments, the
composition is encapsulated in a hard capsule and/or a soft
capsule, wherein a capsule film of the soft capsule may contain
gelatin. In another embodiment, the self-emulsifying composition
further comprises polyoxyethylene hydrogenated castor oil and/or
polyoxyethylene castor oil. In another embodiment, the emulsifier
comprises polyoxyethylene sorbitan fatty acid ester and
polyoxyethylene castor oil. In some embodiments, the pitavastatin,
rosuvastatin, or a salt thereof is pitavastatin calcium or
rosuvastatin calcium. In another embodiment, the lechtin is soybean
lechtin. In another embodiment, the polyoxyethylene sorbitan fatty
acid ester is polyoxyethylene (20) sorbitan monooleate.
In some embodiments, the self-emulsifying composition comprising
E-EPA has improved bioavailability compared as compared to a
standard E-EPA formulation. A standard E-EPA formulation is a
formulation that is not self-emulsifying. In some embodiments, a
self-emulsifying composition comprising about 1.8 to about 3.8 g of
E-EPA has substantially equivalent bioavailability to about 4 g
E-EPA that is not formulated as a self-emulsifying composition. In
some embodiments, the self-emulsifying comprising E-EPA is assessed
for a bioequivalence to about 4 g E-EPA that is not formulated as a
self-emulsifying using for example, U.S. Food and Drug
Administration (FDA) guidelines.
In another embodiment, compositions useful in accordance with
methods of the disclosure are orally deliverable. The terms "orally
deliverable" or "oral administration" herein include any form of
delivery of a therapeutic agent or a composition thereof to a
subject wherein the agent or composition is placed in the mouth of
the subject, whether or not the agent or composition is swallowed.
Thus "oral administration" includes buccal and sublingual as well
as esophageal administration. In one embodiment, the composition is
present in a capsule, for example a soft gelatin capsule.
A composition for use in accordance with the disclosure can be
formulated as one or more dosage units. The terms "dose unit" and
"dosage unit" herein refer to a portion of a pharmaceutical
composition that contains an amount of a therapeutic agent suitable
for a single administration to provide a therapeutic effect. Such
dosage units may be administered one to a plurality (i.e. 1 to
about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as
many times as needed to elicit a therapeutic response.
In one embodiment, compositions of the disclosure, upon storage in
a closed container maintained at room temperature, refrigerated
(e.g. about 5 to about 5-10.degree. C.) temperature, or frozen for
a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months,
exhibit at least about 90%, at least about 95%, at least about
97.5%, or at least about 99% of the active ingredient(s) originally
present therein.
Therapeutic Methods
In one embodiment, the disclosure provides a method for treatment
and/or prevention of cardiovascular-related disease and disorders.
The term "cardiovascular-related disease and disorders" herein
refers to any disease or disorder of the heart or blood vessels
(i.e. arteries and veins) or any symptom thereof. Non-limiting
examples of cardiovascular-related disease and disorders include
hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia,
coronary heart disease, vascular disease, stroke, atherosclerosis,
arrhythmia, hypertension, myocardial infarction, and other
cardiovascular events.
The term "treatment" in relation a given disease or disorder,
includes, but is not limited to, inhibiting the disease or
disorder, for example, arresting the development of the disease or
disorder; relieving the disease or disorder, for example, causing
regression of the disease or disorder; or relieving a condition
caused by or resulting from the disease or disorder, for example,
relieving or treating symptoms of the disease or disorder. The term
"prevention" in relation to a given disease or disorder means:
preventing the onset of disease development if none had occurred,
preventing the disease or disorder from occurring in a subject that
may be predisposed to the disorder or disease but has not yet been
diagnosed as having the disorder or disease, and/or preventing
further disease/disorder development if already present.
In various embodiments, the present disclosure provides methods of
reducing a risk of a cardiovascular event in a subject on statin
therapy. In some embodiments, the methods comprise (a) identifying
a subject on statin therapy and having a fasting baseline
triglyceride level of about 135 mg/dL to about 500 mg/d, wherein
said subject has established cardiovascular disease or has a high
risk of developing cardiovascular disease; and (b) administering to
the subject a composition comprising about 1 g to about 4 g of
eicosapentaenoic acid (free acid) or derivative thereof (ethyl or
methyl ester) per day. The terms "composition" and "pharmaceutical
composition" as provided herein are referenced interchangeably.
In various embodiments, the present disclosure provides methods of
reducing a risk of a cardiovascular event in a subject on statin
therapy. In some embodiments, the methods comprise (a) identifying
a subject on statin therapy and having a fasting baseline
triglyceride level of about 80 mg/dL to about 1500 mg/dL, wherein
said subject has established cardiovascular disease or has a high
risk of developing cardiovascular disease; and (b) administering to
the subject a composition comprising about 1 g to about 4 g of
eicosapentaenoic acid (free acid) or derivative thereof (ethyl or
methyl ester) per day. In some embodiments, the reduction in a risk
of a cardiovascular event is not correlated to a reduction in the
subject's triglyceride levels.
In some embodiments, the present disclosure provides methods of
reducing a risk of a cardiovascular event in a subject on statin
therapy with or without an associated in reduction a baseline
triglyceride level of the subject. As such, a reduction of
cardiovascular events is not correlated to a reduction in the
subject's triglyceride levels. Accordingly, regardless of whether
the subject exhibits a reduction in triglyceride levels, the
subject experiences a reduction in a risk of a cardiovascular
event. In some embodiments, the methods comprise administering to
the subject a composition comprising eicosapentaenoic acid or
derivative thereof, wherein the subject does not exhibit a
statistically significant change in fasting triglyceride levels for
a period of time after administration of the composition. In some
embodiments, the period of time is about 1 year to about 5 years,
about 1 year to about 6 years, about 1 year to about 7 years, about
1 year to about 8 years, or about 1 year to about 9 years. In
another embodiment, the subject exhibits a reduction in fasting
triglycerides at a period time of greater than about 5 years,
greater than about 6 years, greater than about 7 years, greater
than about 8 years, greater than about 9 years, or greater than
about 10 years.
In some embodiments, the present disclosure provides methods of
reducing a risk of total cardiovascular events in a subject on
statin therapy. In some embodiments, the methods comprise
administering to the subject a composition comprising
eicosapentaenoic acid or derivative thereof. Total cardiovascular
events include a first, second, third, fourth, fifth, sixth, eight,
ninth, tenth or more cardiovascular event. In some embodiments, the
subject has not experienced a cardiovascular event, but is at a
high risk for experiencing a cardiovascular event. In some
embodiments, the subject has experienced multiple cardiovascular
events (i.e., a second, third, fourth, or more) and a reduction in
a risk of any subsequent cardiovascular event. In some embodiments,
the total cardiovascular events are reduced by at least about 20%,
at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, or at least about 50%. In some
embodiments, the total cardiovascular events are reduced regardless
of the subject's fasting baseline triglyceride level. For example,
total cardiovascular events are reduced in a subject having a
fasting baseline triglyceride level in a low, medium, or high
tertile. Subjects in the low baseline fasting triglyceride tertile
have triglyceride levels between about 80 mg/dL to about 190 mg/dL
(median triglyceride level of 160 mg/dL), subjects in the medium
baseline fasting triglyceride tertile have triglyceride levels
between about 191 mg/dL to about 250 mg/dL (median triglyceride
level of 215 mg/dL), and lastly, subjects in the high baseline
fasting triglyceride tertile have triglyceride levels between about
251 mg/dL to about 1400 mg/dL (median triglyceride level of 304
mg/dL).
In some embodiments, the present disclosure provides methods of
reducing a cardiovascular event in a subject on statin therapy, the
methods comprising instructing or having instructed a caregiver of
the subject to inquire if the subject has or previously has had
atrial fibrillation and/or flutter, assessing or having assessed
whether the subject has or has previously had symptoms of atrial
fibrillation and/or flutter, monitoring or having monitored the
subject for symptoms of atrial fibrillation and/or flutter, and/or
providing or having provided guidance to a caregiver of the subject
to monitor the subject for symptoms of atrial fibrillation and/or
flutter. In some embodiments, the methods further comprise
administering or having administered to the subject a composition
comprising of eicosapentaenoic acid or derivative thereof per
day.
In some embodiments, the present disclosure provides methods of
reducing an incidence of a cardiovascular event in a subject on
statin therapy. In some embodiments, the methods comprise
administering to the subject a composition comprising
eicosapentaenoic acid or derivative thereof per day, wherein the
subject experiences atrial fibrillation and/or flutter and a
reduction in or no cardiovascular event. For example,
administration of the composition shifts the cardiovascular event
to a less medically severe outcome of atrial fibrillation and/or
flutter. As such, in some embodiments, the subject experiences
atrial fibrillation and/or flutter instead of a cardiovascular
event. In another embodiment, the subject exhibits an increase in
the symptoms of atrial fibrillation and/or flutter and a reduction
in a cardiovascular event as compared to baseline or a placebo
control. In some embodiments, the increase in the symptoms of
atrial fibrillation and/or flutter are statistically significant as
compared to baseline or a placebo control. For example, the
symptoms of atrial fibrillation and/or flutter increase by at least
about 1%, at least about 2%, at least about 3%, at least about 4%,
or at least about 5%. In yet another embodiment, an incidence of
atrial fibrillation and/or flutter requiring hospitalization is
greater in the subject as compared to baseline or a placebo
control. In some embodiments, the subject experiences a reduction
in heart rate.
In some embodiments, the present disclosure provides methods of
reducing a risk of a cardiovascular event in a subject on low,
medium, or high statin therapy. In some embodiments, the methods
comprise administering to the subject a composition comprising
eicosapentaenoic acid or derivative thereof per day and a low,
medium, or high intensity statin therapy. In some embodiments, the
low intensity statin therapy includes about 5 mg to about 10 mg of
simvastatin. In some embodiments, the medium intensity statin
therapy includes about 5 mg to about 10 mg of rosuvastatin, about
10 mg to about 20 mg of atorvastatin, about 20 mg to 40 mg of
simvastatin, or about 10 mg to about 20 mg of simvastatin plus
about 5 mg to about 10 mg of ezetimibe. In some embodiments, the
high intensity statin therapy includes about 20 mg to about 40 mg
rosuvastatin, about 40 mg to about 80 mg of atorvastatin, about 80
mg of simvastatin, or about 40 mg to about 80 mg of simvastatin
plus about 5 mg to about 10 mg of ezetimibe. In some embodiments,
the subject administered the high statin therapy a greater
reduction in a cardiovascular event as compared to a subject in
either a low or medium statin therapy. In some embodiments, the
subject on a medium statin therapy exhibits a greater reduction in
a cardiovascular event as compared to a subject on either a high or
low statin therapy. In some embodiments, the subject on a low
statin therapy exhibits a greater reduction in a cardiovascular
evet as compared to a subject of a high or a medium statin therapy.
In some embodiments, the greater reduction is a reduction of at
least about 5%, at least about 10%, at least about 20%, at least
about 30%, at least about 50%, at least about 60%, at least about
70%, at least about 80%, at least about 90%, at least about 100%,
or more.
In some embodiments, the present disclosure provides methods of
delaying an onset of: (a) non-fatal myocardial infarction; (b)
fatal or non-fatal stroke; (c) cardiovascular death; (d) unstable
angina; (e) coronary revascularization; (f) hospitalization for
unstable angina; (g) composite of cardiovascular death or nonfatal
myocardial infarction; (h) fatal or nonfatal myocardial infarction;
(i) non-elective coronary revascularization represented the
composite of emergent or urgent classifications; (j) cardiovascular
death; (k) unstable angina determined to be caused by myocardial
ischemia by invasive or non invasive testing and requiring emergent
hospitalization; and/or (l) a composite of total mortality,
nonfatal myocardial infarction, and/or nonfatal stroke. An onset of
a disease and/or cardiovascular event refers to a first appearance
of a sign and/or symptom of the cardiovascular event. In some
embodiments, delaying an onset of a cardiovascular event prevents
the subject from experiencing the cardiovascular event and/or
developing any further symptoms of the cardiovascular event. In
some embodiments, the methods comprise administering a composition
comprising eicosapentaenoic acid or derivative thereof per day.
In yet another embodiment, the present disclosure provides methods
of reducing risk of occurrence of one or more components of a
3-point composite endpoint composed of cardiovascular death,
non-fatal myocardial infarction, or non-fatal stroke in a subject
on statin therapy or reducing risk occurrence of one or more
components of a 5-point composite endpoint composed of
cardiovascular death, non-fatal stroke, non-fatal myocardial
infarction, coronary revascularization, or unstable angina
requiring hospitalization in a subject on statin therapy. In some
embodiments, each of the individual components of 3-point composite
and 5-poinst composite endpoints is reduced. For example, each of
cardiovascular death, non-fatal myocardial infarction, and
non-fatal stroke are reduced within the combination. In some
embodiments, the methods comprise administering a composition
comprising eicosapentaenoic acid or derivative thereof per day. In
some embodiments, the 3-point composite endpoint or the 5-point
composite endpoint is reduced by at least about 20%, at least about
30%, at least about 40%, or at least about 50%. In some
embodiments, each of the individual components of the 3-point
composite endpoint or the 5-point composite endpoint is reduced by
at least about 20%, at least about 30%, at least about 40%, or at
least about 50%.
In another embodiment, the present disclosure provides methods of
reducing a cardiovascular event, the methods comprising
administering a composition comprises EPA or derivative thereof
that is formulated such that when administered to the subject, the
composition provides an amount of EPA or derivative thereof
effective to achieve an efficacy equivalent dose to about a 4 g
dose of EPA or derivative thereof but at a lower daily dose of EPA
or derivative thereof. In some embodiments, the lower daily dose of
the EPA or derivative thereof of is not more than about 3.8 g, not
more than about 3.6 g, not more than about 3.4 g, not more than
about 3.2 g, not more than about 3 g, not more than about 2.8 g,
not more than about 2.6 g, or not more than about 2.5 g. In some
embodiments, the lower daily dose of the EPA or derivative thereof
is reduced by at least about 10%, at least about 20%, at least
about 30%, at least about 40% in the subject as compared to a
baseline or placebo control. In one embodiment, administering the
composition to the subject results in an improved pharmacokinetic
profile in the subject as compared a control subject, wherein the
subject and control subject are in either or fed or fasting state,
and wherein the pharmacokinetic profile is defined by maximum serum
concentration (C.sub.max) and area under the curve (AUC). In some
embodiments, the control subject is on a statin therapy and
administered a placebo or other fatty acid composition such as
Lovaza comprised of 365 mg of E-EPA and 375 mg of E-DHA.
In some embodiments, the present disclosure provides methods of
reducing a cardiovascular event in a subject on a statin therapy,
the methods comprising administering a composition comprising EPA
or derivative thereof, wherein the subject does not experience an
adverse event. Non-limiting examples of adverse events include back
pain, nasopharyngitis, arthralgia, bronchitis, oedema peripheral,
dyspnea, osteoarthritis, cataract, fatigue, constipation,
musculoskeletal pain, gout, fall, type 2 diabetes mellitus,
gastroesophageal reflux disease, insomnia, acute kidney injury,
hepatic disorders, bleeding related disorders (e.g.,
gastrointestinal or central nervous system bleeding), newly
diagnosed diabetes, newly diagnosed neoplasms (e.g., benign or
malignant neoplasms), upper respiratory tract infection, chest
pain, peripheral edema, pneumonia, influenza, urinary tract
infection, cough, dizziness, pain in an extremity, angina pectoris,
and anemia.
In yet another embodiment, the present disclosure provides methods
of reducing a cardiovascular event in a subject on a statin therapy
and less than about 65 years of age or greater than about 65 years
of age, the method comprising administering to the subject a
composition comprising EPA or derivative thereof. In some
embodiments, the degree by which the cardiovascular event is
reduced is dependent upon the age of the subject. For example, in
some embodiments, the subject less than about 65 years of age
exhibits a statistically significant reduction in a cardiovascular
event as compared to a subject greater than about 65 years of age.
Conversely, in some embodiments, the subject greater than about 65
years of age exhibits a statistically significant reduction in a
cardiovascular event as compared to a subject less than about 65
years of age. As such, in some embodiments, the methods for
reducing a cardiovascular event are correlated to the age of the
subject.
In some embodiments, the present disclosure provides methods of
reducing a cardiovascular event in a subject on a statin therapy,
the methods comprising administering to the subject a
self-emulsifying composition. In some embodiments, the
self-emulsifying composition comprises at least one compound
selected from the group consisting of an omega-3 fatty acid and
derivative thereof (e.g., pharmaceutically acceptable salt and/or
ester). In another embodiment, the composition comprises an
emulsifier. In some embodiments, the emulsifier has a hydrophilic
lipophilic balance (HLB) of at least about 10. Non-limiting
examples of emulsifiers include polyoxyethylene hydrogenated castor
oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene
castor oil, polyethylene glycol fatty acid ester, polyoxyethylene
polyoxypropylene glycol, sucrose fatty acid ester, and lecithin. In
another embodiment, the omega-3 fatty acids or derivative thereof
are present in an amount of about 50% to about 95% by weight of the
total weight of the composition or by weight of the total fatty
acids of the total composition. In some embodiments, the omega-3
fatty acid is EPA and/or DHA. In some embodiments, the EPA is
present in amount at least about 95%, by weight, of all fatty acids
present in the self-emulsifying composition. In another embodiment,
the composition contains substantially no DHA. In yet another
embodiment, the composition contains substantially no ethanol.
In some embodiments, the subject has symptoms of atrial
fibrillation and/or flutter. Non-limiting examples of symptoms of
atrial fibrillation and/or flutter include heart rate greater than
about 100 beats per minute (bpm); heart palpitations; shortness of
breath; pain, pressure, tightness or discomfort in chest;
dizziness; lightheadedness; or fainting. In some embodiments the
subject has a risk factor for atrial fibrillation and/or flutter
including (a) heart failure; (b) previous heart attack; (c) heat
valve abnormalities; (d) high blood pressure; (e) thyroid
dysfunction; (f) chronic lung disease; (g) diabetes; (h) obesity;
and (i) congenital heart disease.
In some embodiments, the methods further comprising monitoring a
subject for atrial fibrillation and/or flutter or for symptoms of
atrial fibrillation and/or flutter. Non-limiting examples for
methods to monitor atrial fibrillation and/or flutter include
electrocardiograms (ECGs), implantable pacemakers, implantable
cardioverter defibrillators, and/or subcutaneous implantable
cardiac monitors.
In some embodiments, the subject has atrial fibrillation and/or
flutter or has symptoms of atrial fibrillation and/or flutter and
has been determined to have a heart rate of about 80 bpm, about 85,
bpm, about 90 bpm, about 95 bpm, about 100 bpm, about 105 bpm,
about 110 bpm, about 115 bpm, about 120 bpm, about 125 bpm, about
130 bpm, about 135 bmp, about 140 bmp, about 145 bmp, about 150
bpm, about 155 bpm, about 160 bpm, about 165 bpm, about 170 bpm,
about 175 bpm, about 180 bpm, about 185, bpm, about 190 bpm or a
heart rate between about 80 bpm to about 100 bpm, about 90 bpm to
about 200 bpm, about 100 bpm to about 175 bpm, about 120 bpm to
about 180 bpm, or about 85 bpm to about 200 bpm.
In some embodiments, the present disclosure provides methods of
reducing blood pressure in a subject. In one embodiment,
administration of 4 g per day of comprising EPA or derivative
thereof (E-EPA) for a period at least 1, 2, 3 or 4 year reduces
systolic blood pressure by at least about 1 mm Hg and reduces
diastolic blood pressure aby at least about 0.5 mm Hg, compared to
baseline or a placebo control subject.
In some embodiments, the subject has a fasting baseline
triglyceride level of about 135 mg/dL to about 500 mg/dL, for
example about 135 mg/dL to about 500 mg/dL, about 150 mg/dL to
about 500 mg/dL, about 200 mg/dL to about 499 mg/dL or about 200
mg/dL to <500 mg/dL. In some embodiments, the subject has a
fasting baseline triglyceride level of about 50 mg/dL to about 1500
mg/dL, for example about 50 mg/dL to about 1500 mg/dL, about 80
mg/dL to about 1500 mg/dL, about 50 mg/dL to about 190 mg/dl, about
80 mg/dL to about 190 mg/dl, about 190 mg/dL to about 250 mg/dL,
about 250 mg/dL to about 1400 mg/dL. In one embodiment, the subject
has a fasting baseline triglyceride level of about 80 mg/dL to
about 1400 mg/dL. In some embodiments, the subject or subject group
has a baseline triglyceride level (or median baseline triglyceride
level in the case of a subject group), fed or fasting, of about 50
mg/dL, about 55 mg/dL, about 60 rng/dL, about 65 mg/dL, about 70
mg/dL, about 75 mg/dL, about 80 mg/dL, about 85 mg/dL, about 90
mg/dL, about 95 mg/dL, about 100 mg/dL, about 105 mg/dL, about 110
mg/dL, about 115 mg/dL, about 120 mg/dL, about 125 mg/dL, about 130
mg/dL, about 135 mg/dL, about 140 mg/dL, about 145 mg/dL, about 150
mg/dL, about 155 mg/dL, about 160 mg/dL, about 165 mg/dL, about 170
mg/dL, about 175 mg/dL, about 180 mg/dL, about 185 mg/dL, about 190
mg/dL, about 195 mg/dL, about 200 mg/dL, about 205 mg/dL, about 210
mg/dL, about 215 mg/dL, about 220 mg/dL, about 225 mg/dL, about 230
mg/dL, about 235 mg/dL, about 240 mg/dL, about 245 mg/dL, about 250
mg/dL, about 255 mg/dL, about 260 mg/dL, about 265 mg/dL, about 270
mg/dL, about 275 mg/dL, about 280 mg/dL, about 285 mg/dL, about 290
mg/dL, about 295 mg/dL, about 300 mg/dL, about 305 mg/dL, about 310
mg/dL, about 315 mg/dL, about 320 mg/dL, about 325 mg/dL, about 330
mg/dL, about 335 mg/dL, about 340 mg/dL, about 345 mg/dL, about 350
mg/dL, about 355 mg/dL, about 360 mg/dL, about 365 mg/dL, about 370
mg/dL, about 375 mg/dL, about 380 mg/dL, about 385 mg/dL, about 390
mg/dL, about 395 mg/dL, about 400 mg/dL, about 405 mg/dL, about 410
mg/dL, about 415 mg/dL, about 420 mg/dL, about 425 mg/dL, about 430
mg/dL, about 435 mg/dL, about 440 mg/dL, about 445 mg/dL, about 450
mg/dL, about 455 mg/dL, about 460 mg/dL, about 465 mg/dL, about 470
mg/dL, about 475 mg/dL, about 480 mg/dL, about 485 mg/dL, about 490
mg/dL, about 495 mg/dL, about 500 mg/dL, about 1000 mg/dL, about
1100 mg/dL, about 1200 mg/dL, about 1300 mg/dL, about 1400 mg/dL,
about 1500 mg/dL, about 2000 mg/dL, about 2500 mg/dL, about 3000
mg/dL, about 3500 mg/dL, about 4000 mg/dL, about 4500 mg/dL, about
5000 mg/dL, or greater than about 5000 mg/dL. In some embodiments,
the subject or subject group has a baseline triglyceride level (or
median baseline triglyceride level in the case of a subject group),
fed or fasting, greater than or equal to 80 mg/dL, greater than or
equal to about 100 mg/dL, greater than or equal to about 120 mg/dL
greater than or equal to about 150 mg/dL, greater than or equal to
about 175 mg/dL, greater than or equal to about 250 mg/dL, or
greater than equal to about 500 mg/dL, for example about 190 mg/dL
to about 250 mg/dL, about 80 mg/dL to about 190 mg/dL, about 250
mg/dL to about 1400 mg/dL, about 200 mg/dL to about 500 mg/dL,
about 300 mg/dL to about 1800 mg/dL, about 500 mg/dL to about 1500
mg/dL, or about 80 mg/dL to about 1500 mg/dL.
In some embodiments, the subject or subject group is also on stable
therapy with a statin (with or without ezetimibe). In some
embodiments, the subject or subject group also has established
cardiovascular disease, or is at high risk for establishing
cardiovascular disease. In some embodiments, the subject's statin
therapy includes administration of one or more statins. For
example, and without limitation, the subject's statin therapy may
include one or more of: atorvastatin, fluvastatin, lovastatin,
pitavastatin, pravastatin, rosuvastatin, and simvastatin. In some
embodiments, the subject is additionally administered one or more
of: amlodipine, ezetimibe, niacin, and sitagliptin. In some
embodiments, the subject's statin therapy includes administration
of a statin and ezetimibe. In some embodiments, the subject's
statin therapy includes administration of a statin without
ezetimibe.
In some embodiments, the statin therapy is classified as
monotherapies, combinations, and or
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase
inhibitor combinations. In some embodiments, the monotherapies
include simvastatin, lovastatin, pravastatin, fluvastatin,
atorvastatin, cerivastatin, rosuvastatin, or pitavastatin. In some
embodiments, the combinations include lovastatin and nicotinic
acid, simvastatin and ezetimibe, pravastatin and fenofibrate,
simvastatin and fenofibrate, atorvastatin and ezetimibe, or
rosuvastatin and ezetimibe. In some embodiments, the HMG CoA
inhibitor combinations include simvastatin and acetylsalicylic
acid; pravastatin and acetylsalicylic acid; atorvastatin and
amlodipine; simvastatin, acetylsalicylic acid, and ramipril;
rosuvastatin and acetylsalicylic acid; atorvastatin,
acetylsalicylic acid, and ramipril; rosuvastatin, amlodipine, and
lisinopril; atorvastatin and acetylsalicylic acid; rosuvastatin and
amlodipine; rosuvastatin and valsartan; atorvastatin, amlodipine,
and perindopril; atorvastatin, acetylsalicylic acid, and
perindopril; rosuvastatin, perindopril, and indapamide;
rosuvastatin, amlodipine, and perindopril; or atorvastatin and
perindopril.
In some embodiments, the statin therapy is a low, medium (i.e.,
moderate), or high intensity statin therapy. In some embodiments,
the low intensity statin therapy includes about 5 mg to about 10 mg
of simvastatin. In some embodiments, the medium intensity statin
therapy includes about 5 mg to about 10 mg of rosuvastatin, about
10 mg to about 20 mg of atorvastatin, about 20 mg to about 40 mg of
simvastatin, or about 10 mg to about 20 mg of simvastatin plus
about 5 mg to about 10 mg of ezetimibe. In some embodiments, the
high intensity statin therapy includes about 20 mg to about 40 mg
rosuvastatin, about 40 mg to about 80 mg of atorvastatin, about 80
mg of simvastatin, or about 40 mg to about 80 mg of simvastatin
plus about 5 mg to about 10 mg of ezetimibe.
In some embodiments, the subject's statin therapy does not include
administration of 200 mg or more per day of niacin and/or fibrates.
In some embodiments, the subject is not on concomitant omega-3
fatty acid therapy (e.g., is not being administered or
co-administered a prescription and/or over-the-counter composition
comprising an omega-3 fatty acid active agent). In some
embodiments, the subject is not administered or does not ingest a
dietary supplement comprising an omega-3 fatty acid.
In some embodiments, the subject has established cardiovascular
(CV) disease ("CV disease" or "CVD"). The status of a subject as
having CV disease can be determined by any suitable method known to
those skilled in the art. In some embodiments, a subject is
identified as having established CV disease by the presence of any
one of: documented coronary artery disease, documented
cerebrovascular disease, documented carotid disease, documented
peripheral arterial disease, or combinations thereof. In some
embodiments, a subject is identified as having CV disease if the
subject is at least 45 years old and: (a) has one or more stenosis
of greater than 50% in two major epicardial coronary arteries; (b)
has had a documented prior MI; (c) has been hospitalized for
high-risk NSTE ACS with objective evidence of ischemia (e.g.,
ST-segment deviation and/or biomarker positivity); (d) has a
documented prior ischemic stroke; (e) has symptomatic artery
disease with at least 50% carotid arterial stenosis; (f) has
asymptomatic carotid artery disease with at least 70% carotid
arterial stenosis per angiography or duplex ultrasound; (g) has an
ankle-brachial index ("ABI") of less than 0.9 with symptoms of
intermittent claudication; and/or (h) has a history of aorto-iliac
or peripheral arterial intervention (catheter-based or
surgical).
In some embodiments, the subject or subject group being treated in
accordance with methods of the disclosure has a high risk for
developing CV disease. For example and without limitation, a
subject or subject group has a high risk for developing CV disease
if the subject or subject in a subject group is age about 50 or
older, has diabetes mellitus (Type 1 or Type 2), and at least one
of: (a) is a male age about 55 or older or a female age about 65 or
older; (b) is a cigarette smoker or was a cigarette smoker who
stopped less than about 3 months prior; (c) has hypertension (e.g.,
a blood pressure of about 140 mmHg systolic or higher, or greater
than about 90 mmHg diastolic): (d) has an HDL-C level of
.ltoreq.about 40 mg/dL for men or about 50 mg/dL for women; (e) has
an hsCRP level of >about 3.0 mg/L; (f) has renal dysfunction
(e.g., a creatinine clearance ("CrCL") of greater than about 30
mL/min and less than about 60 mL/min); (g) has retinopathy (e.g.,
defined as any of: non-proliferative retinopathy, preproliferative
retinopathy, proliferative retinopathy, maculopathy, advanced
diabetic eye disease, or history of photocoagulation); (h) has
microalbuminuria (e.g., a positive micral or other strip test, an
albumin/creatinine ratio of >about 2.5 mg/mmol, or an albumin
excretion rate on timed collection of >about 20 mg/min all on at
least two successive occasions); (i) has macroalbuminuria (e.g.,
Albustix or other dip stick evidence of gross proteinuria, an
albumin/creatinine ratio of about 25 mg/mmol, or an albumin
excretion rate on timed collection of .gtoreq.about 200 mg/min all
on at least two successive occasions); and/or (j) has an
ankle-brachial index of <about 0.9 without symptoms of
intermittent claudication.
In some embodiments, the subject's baseline lipid profile is
measured or determined prior to administering the composition to
the subject. Lipid profile characteristics can be determined by any
suitable method known to those skilled in the art including, for
example, by testing a fasting or non-fasting blood sample obtained
from the subject using standard blood lipid profile assays. In some
embodiments, the subject has one or more of: a baseline non-HDL-C
value of about 200 mg/dL to about 300 mg/dL; a baseline total
cholesterol value of about 250 mg/dL to about 300 mg/dL; a baseline
VLDL-C value of about 140 mg/dL to about 200 mg/dL; a baseline
HDL-C value of about 10 mg/dL to about 30 mg/dL; a baseline LDL-C
value of about 40 mg/dL to about 100 mg/dL; and/or a baseline hsCRP
level of about 2 mg/dL or less.
In some embodiments, the cardiovascular event for which risk is
reduced is one or more of: cardiovascular death; nonfatal
myocardial infarction; nonfatal stroke; coronary revascularization;
unstable angina (e.g., unstable angina determined to be caused by
myocardial ischemia by, for example, invasive or non-invasive
testing, and requiring hospitalization); cardiac arrest; peripheral
cardiovascular disease requiring intervention, angioplasty, bypass
surgery or aneurysm repair; death; sudden cardiac death, sudden
death, and onset of new congestive heart failure. In some
embodiments, the cardiovascular event is a first, second, third,
fourth, or more cardiovascular event experienced by the
subject.
In some embodiments, the subject is administered about 1 g to about
4 g of the composition per day for about 4 months, about 1 year,
about 1.25 years, about 1.5 years, about 1.75 years, about 2 years,
about 2.25 years, about 2.5 years, about 2.75 years, about 3 years,
about 3.25 years, about 3.5 years, about 3.75 years, about 4 years,
about 4.25 years, about 4.5 years, about 4.75 years, about 5 years,
or more than about 5 years. Thereafter, in some embodiments the
subject exhibits one or more of
(a) a reduction in triglyceride levels compared to baseline or
control;
(b) a reduction in Apo B levels compared to baseline or
control;
(c) an increase in HDL-C levels compared to baseline or
control;
(d) no increase or increase in LDL-C levels compared to baseline or
control;
(e) a reduction in LDL-C levels compared to baseline;
(f) a reduction in non-HDL-C levels compared to baseline or
control;
(g an increase in non-HDL-C levels compared to baseline or
control;
(h) a reduction in VLDL-C levels compared to baseline or
control;
(i) a reduction in total cholesterol levels compared to baseline or
control;
(j) a reduction in high sensitivity C-reactive protein (hsCRP)
levels compared to baseline or control;
(k) a reduction in high sensitivity troponin (hsTnT) levels
compared to baseline or control;
(l) a reduction in a risk of cardiovascular death, coronary
revascularization, unstable angina, myocardial infarction, and/or
stroke as compared to baseline or control;
(m) a reduction in a risk of cardiac arrest as compared to baseline
or control;
(n) a reduction in a risk of sudden death as compared to baseline
or control;
(o) a reduction in a first, second, third, fourth, or more
cardiovascular event as compared to baseline or placebo
control;
(p) a reduction in total cardiovascular events as compared to
baseline or control;
(q) a reduction in a 3-point composite endpoint of cardiovascular
death, non-fatal myocardial infarction, or non-fatal stroke as
compared to baseline or control;
(r) a reduction in a 5-point composite endpoint of cardiovascular
death, non-fatal stroke, non-fatal myocardial infarction, coronary
revascularization, or unstable angina as compared to baseline or
control;
(s) an increase in atrial fibrillation and/or flutter as compared
to baseline or control;
(t) an increase in symptoms of atrial fibrillation and/or flutter
as compared to baseline or control;
(u) a reduction of total mortality (i.e., death from any cause) as
compared to baseline or control;
(v) a reduction in a composite of total mortality, non-fatal
myocardial infarction, and stroke as compared to baseline or
placebo control;
(w) a reduction in new congestive heart failure (CHF) or new CHF as
the primary cause of hospitalization as compared to baseline or
control;
(x) a reduction in transient ischemic attack as compared to
baseline or control;
(y) a reduction in a risk of amputation for peripheral vascular
disease (PVD) as compared to baseline or control;
(z) a reduction in a risk of carotid revascularization as compared
to baseline or control;
(aa) a reduction in cardiac arrhythmias as compared to baseline or
control;
(bb) a reduction in hypertension as compared to baseline or
control;
(cc) a reduction in type 1 or type 2 diabetes as compared to
baseline or control; and/or
(dd) a reduction in body weight and/or weight circumference as
compared to baseline or control;
In one embodiment, methods of the present disclosure comprise
measuring baseline levels of one or more markers set forth in
(a)-(dd) above prior to dosing the subject or subject group. In
another embodiment, the methods comprise administering a
composition as disclosed herein to the subject after baseline
levels of one or more markers set forth in (a)-(dd) are determined,
and subsequently taking an additional measurement of said one or
more markers.
In another embodiment, upon treatment with a composition of the
present disclosure, the subject exhibits one or more of:
(a) a reduction in triglyceride levels of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, or at least about 55%
as compared to baseline or control;
(b) a reduction in Apo B levels of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, at least about 55% or at least
about 75% as compared to baseline or control;
(c) an increase in HDL-C levels of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, at least about 55% or at least
about 75% as compared to baseline or control;
(d) no increase or an increase in LDL-C levels of less than 30%,
less than 20%, less than 10%, less than 5% as compared to baseline
or control; and/or
(e) a reduction in LDL-C levels of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, or at least about 55% as
compared to baseline or control.
(f) a reduction in non-HDL-C levels of at least about 1%, at least
about 3%, at least about 5%, at least about 10%, at least about
15%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, or at
least about 50% as compared to baseline or control;
(g) an increase in non-HDL-C levels of less than 30%, less than
20%, less than 10%, less than 5% (actual % change or median %
change), or no increase in non-HDL-C levels as compared to baseline
or control;
(h) a reduction in VLDL-C levels of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, or at least about 100%
compared to baseline or control;
(i) a reduction in total cholesterol levels of at least about 5%,
at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55% or at least about 75% as compared to baseline or control;
and/or
(j) a reduction in hsCRP levels of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, or at least about 100% as
compared to baseline or control;
(k) a reduction in high sensitivity troponin (hsTnT) levels of at
least about 5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, or
at least about 100% as compared to baseline or control;
(1) a reduction in a risk of cardiovascular death, coronary
revascularization, unstable angina, myocardial infarction, and/or
stroke of at least about 5%, at least about 10%, at least about
15%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55%, at least about 75%, at least about
80%, at least about 85%, at least about 90%, at least about 95%, or
at least about 100% as compared to baseline or control;
(m) a reduction in a risk of cardiac arrest of at least about 5%,
at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, at least about 95%, or at least about 100% as
compared to baseline or control;
(n) a reduction in a risk of sudden cardiac death and/or sudden
death of at least about 5%, at least about 10%, at least about 15%,
at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55%, at least about 75%, at least about
80%, at least about 85%, at least about 90%, at least about 95%, or
at least about 100% as compared to baseline or control;
(o) a reduction in a first, second, third, fourth, or more
cardiovascular event experienced by the subject of at least about
5%, at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, at least about 95%, or at least about 100% as
compared to baseline or control;
(p) a reduction in total cardiovascular events of at least about
5%, at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, at least about 95%, or at least about 100% as
compared to baseline or control;
(q) a reduction in a 3-point composite endpoint of cardiovascular
death, non-fatal myocardial infarction, or non-fatal stroke of at
least about 5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about 75%, at least about 80%, at least
about 85%, at least about 90%, at least about 95%, or at least
about 100% as compared to baseline or control;
(r) a reduction in a 5-point composite endpoint of cardiovascular
death, non-fatal stroke, non-fatal myocardial infarction, coronary
revascularization, or unstable angina of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, at least about 55%, at
least about 75%, at least about 80%, at least about 85%, at least
about 90%, at least about 95%, or at least about 100% as compared
to baseline or control;
(s) an increase in atrial fibrillation and/or flutter of at least
about 1%, at least about 1.5%, at least about 2%, at least about
2.5%, at least about 3%, at least about 3.5%, at least about 4%, at
least about 4.5%, at least about 5%, at least about 5.5%, at least
about 6%, at least about 6.5%, at least about 7%, at least about
7.5%, at least about 8%, at least about 8.5%, at least about 9%, at
least about 9.5%, or at least about 10% as compared to baseline or
control;
(t) an increase in symptoms of atrial fibrillation and/or flutter
of at least about 1%, at least about 1.5%, at least about 2%, at
least about 2.5%, at least about 3%, at least about 3.5%, at least
about 4%, at least about 4.5%, at least about 5%, at least about
5.5%, at least about 6%, at least about 6.5%, at least about 7%, at
least about 7.5%, at least about 8%, at least about 8.5%, at least
about 9%, at least about 9.5%, or at least about 10% as compared to
baseline or control;
(u) a reduction of total mortality (i.e., death from any cause) of
at least about 5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about 75%, at least about 80%, at least
about 85%, at least about 90%, at least about 95%, or at least
about 100% as compared to baseline or control;
(v) a reduction in a composite of total mortality, non-fatal
myocardial infarction, and stroke of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, at least about 55%, at least
about 75%, at least about 80%, at least about 85%, at least about
90%, at least about 95%, or at least about 100% as compared to
baseline or control;
(w) a reduction in new CHF or new CHF as the primary cause of
hospitalization of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about
30%, at least about 35%, at least about 40%, at least about 45%, at
least about 50%, at least about 55%, at least about 75%, at least
about 80%, at least about 85%, at least about 90%, at least about
95%, or at least about 100% as compared to baseline or control;
(x) a reduction in transient ischemic attack of at least about 5%,
at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, at least about 95%, or at least about 100% as
compared to baseline or control;
(y) a reduction in a risk of amputation for PVD of at least about
5%, at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, at least about 95%, or at least about 100% as
compared to baseline or control;
(z) a reduction in a risk of carotid revascularization of at least
about 5%, at least about 10%, at least about 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 75%, at least about 80%, at least about
85%, at least about 90%, at least about 95%, or at least about 100%
as compared to baseline or control;
(aa) a reduction in cardiac arrhythmias of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, at least about 55%, at
least about 75%, at least about 80%, at least about 85%, at least
about 90%, at least about 95%, or at least about 100% as compared
to baseline or control;
(bb) a reduction in hypertension of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, at least about 55%, at least
about 75%, at least about 80%, at least about 85%, at least about
90%, at least about 95%, or at least about 100% as compared to
baseline or control;
(cc) a reduction in type 1 or type 2 diabetes of at least about 5%,
at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, at least about 95%, or at least about 100% as
compared to baseline or control; and/or
(dd) a reduction in body weight and/or weight circumference of at
least about 5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about 75%, at least about 80%, at least
about 85%, at least about 90%, at least about 95%, or at least
about 100% as compared to baseline or control.
In one embodiment, the subject or subject group being treated has a
baseline EPA blood level on a (mol %) basis of less than 2.6, less
than 2.5, less than 2.4, less than 2.3, less than 2.2, less than
2.1, less than 2, less than 1.9, less than 1.8, less than 1.7, less
than 1.6, less than 1.5, less than 1.4, less than 1.3, less than
1.2, less than 1.1 or less than 1.
In another embodiment, the subject or subject group being treated
has a baseline triglyceride level (or median baseline triglyceride
level in the case of a subject group), fed or fasting, of about 135
mg/dL to about 500 mg/dL. In some embodiments, the subject or
subject group being treated has a baseline triglyceride level (or
median baseline triglyceride level in the case of a subject group),
fed or fasting, of about 80 mg/dL to about 1500 mg/dL. In some
embodiments, the subject or subject group being treated in
accordance with methods of the disclosure is on stable therapy with
a statin (with or without ezetimibe). As used herein, the phrase
"on stable therapy with a statin" means that the subject or subject
group has been on the same daily dose of the same statin for at
least 28 days and, if applicable, the same daily dose of ezetimibe
for at least 28 days. In some embodiments, the subject or subject
group on stable statin therapy has an LDL-C level of about 40 mg/dL
to about 100 mg/dL.
In some embodiments, safety laboratory tests of subject blood
samples include one or more of: hematology with complete blood
count ("CBC"), including RBC, hemoglobin (Hgb), hematocrit (Hct),
white cell blood count (WBC), white cell differential, and platelet
count; and biochemistry panel including total protein, albumin,
alkaline phosphatase, alanine aminotransferase (ALT/SGPT),
aspartate aminotransferase (AST/SGOT), total bilirubin, glucose,
calcium, electrolytes, (sodium, potassium, chloride), blood urea
nitrogen (BUN), serum creatinine, uric acid, creatine kinase, and
HbA.sub.1c.
In some embodiments, a fasting lipid panel associated with a
subject includes TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C. In
some embodiments, LDL-C is calculated using the Friedewald
equation, or is measured by preparative ultracentrifugation (Beta
Quant) if the subject's triglyceride level is greater than 400
mg/dL. In some embodiments, LDL-C is measured by
ultracentrifugation (Beta Quant) at randomization and again after
about one year after randomization.
In some embodiments, a biomarker assay associated with blood
obtained from a subject includes hsCRP, Apo B and hsTnT.
In some embodiments, a medical history associated with a subject
includes family history, details regarding all illnesses and
allergies including, for example, date(s) of onset, current status
of condition(s), and smoking and alcohol use.
In some embodiments, demographic information associated with a
subject includes day, month and year of birth, race, and
gender.
In some embodiments, vital signs associated with a subject include
systolic and diastolic blood pressure, heart rate, respiratory
rate, and body temperature (e.g., oral body temperature).
In some embodiments, a physical examination of a subject includes
assessments of the subject's general appearance, skin, head, neck,
heart, lung, abdomen, extremities, and neuromusculature.
In some embodiments, the subject's height and weight are measured.
In some embodiments, the subject's weight is recorded with the
subject wearing indoor clothing, with shoes removed, and with the
subject's bladder empty.
In some embodiments, a waist measurement associated with the
subject is measured. In some embodiments, the waist measurement is
determined with a tape measure at the top of the subject's hip
bone.
In some embodiments, an electrocardiogram associated with the
subject is obtained. In some embodiments, an ECG is obtained every
year during the treatment/follow-up portion of the study. In some
embodiments, the ECG is a 12-lead ECG. In some embodiments, the ECG
is analyzed for detection of silent MI.
In some embodiments, subjects randomly assigned to the treatment
group receive 4 g per day of a composition comprising at least 96%
by weight of eicosapentaenoic acid ethyl ester. In some
embodiments, the composition is encapsulated in a gelatin capsule.
In some embodiments, subjects in this treatment group continue to
take 4 g per day of the composition for about 1 year, about 2
years, about 3 years, about 4 years, about 4.75 years, about 5
years, about 6 years, about 7 years, about 8 years, about 9 years,
about 10 years, or more than about 10 years. In some embodiments, a
median treatment duration is planned to be about 4 years.
In some embodiments, the present disclosure provides a method of
reducing a risk of cardiovascular events in a subject. In some
embodiments, the method comprises administering to the subject a
composition comprising at least 96% by weight of eicosapentaenoic
acid ethyl ester. In some embodiments, the subject is administered
about 1 g to about 4 g of the composition per day.
In some embodiments, the reduced risk of CV events is indicated or
determined by comparing an amount of time (e.g., an average amount
of time) associated with a subject or subject group from first
dosing to a first CV event selected from the group consisting of:
CV death, nonfatal MI, nonfatal stroke, coronary revascularization,
and hospitalization (e.g., emergent hospitalization) for unstable
angina determined to be caused by myocardial ischemia (e.g., by
invasive or non-invasive testing), to an amount of time (e.g., an
average amount of time) associated with a placebo or untreated
subject or group of subjects from first dosing with a placebo to a
first CV event selected from the group consisting of: CV death,
nonfatal MI, nonfatal stroke, coronary revascularization, and
hospitalization (e.g., emergent hospitalization) for unstable
angina determined to be caused by myocardial ischemia (e.g., by
invasive or non-invasive testing), wherein said placebo does not
include eicosapentaenoic acid ethyl ester. In some embodiments, the
amount of time associated with the subject or group of subjects are
compared to the amount of time associated with the placebo or
untreated subject or group of subjects are compared using a
log-rank test. In some embodiments, the log-rank test includes one
or more stratification factors such as CV Risk Category, use of
ezetimibe, and/or geographical region.
In some embodiments, the present disclosure provides a method of
reducing risk of CV death in a subject on stable statin therapy and
having CV disease or at high risk for developing CV disease,
comprising administering to the subject a composition as disclosed
herein.
In another embodiment, the present disclosure provides a method of
reducing risk of recurrent nonfatal myocardial infarction
(including silent MI) in a subject on stable statin therapy and
having CV disease or at high risk for developing CV disease,
comprising administering to the patient one or more compositions as
disclosed herein.
In some embodiments, the present disclosure provides a method of
reducing risk of nonfatal stroke in a subject on stable statin
therapy and having CV disease or at high risk for developing CV
disease, comprising administering to the subject a composition as
disclosed herein.
In some embodiments, the present disclosure provides a method of
reducing risk of coronary revascularization in a subject on stable
statin therapy and having CV disease or at high risk for developing
CV disease, comprising administering to the subject a composition
as disclosed herein.
In some embodiments, the present disclosure provides a method of
reducing risk of developing unstable angina caused by myocardial
ischemia in a subject on stable statin therapy and having CV
disease or at high risk for developing CV disease, comprising
administering to the subject a composition as disclosed herein.
In some embodiments, the present disclosure provides a method of
reducing risk of cardiac arrest in a subject on stable statin
therapy and having CV disease or at high risk for developing CV
disease, comprising administering to the subject a composition as
disclosed herein.
In some embodiments, the present disclosure provides a method of
reducing risk of sudden cardiac death and/or sudden death in a
subject on stable statin therapy and having CV disease or at high
risk for developing CV disease, comprising administering to the
subject a composition as disclosed herein.
In some embodiments, the present disclosure provides a method of
reducing risk of first, second, third, fourth, or more
cardiovascular event in a subject on stable statin therapy and
having CV disease or at high risk for developing CV disease,
comprising administering to the subject a composition as disclosed
herein
In another embodiment, any of the methods disclosed herein are used
in treatment or prevention of a subject or subjects that consume a
traditional Western diet. In one embodiment, the methods of the
disclosure include a step of identifying a subject as a Western
diet consumer or prudent diet consumer and then treating the
subject if the subject is deemed a Western diet consumer. The term
"Western diet" herein refers generally to a typical diet consisting
of, by percentage of total calories, about 45% to about 50%
carbohydrate, about 35% to about 40% fat, and about 10% to about
15% protein. A Western diet may alternately or additionally be
characterized by relatively high intakes of red and processed
meats, sweets, refined grains, and desserts, for example more than
50%, more than 60% or more or 70% of total calories come from these
sources.
In another embodiment, a composition as described herein is
administered to a subject once or twice per day. In another
embodiment, 1, 2, 3 or 4 capsules, each containing about 1 g of a
composition as described herein, are administered to a subject
daily. In another embodiment, 1 or 2 capsules, each containing
about 1 g of a composition as described herein, are administered to
the subject in the morning, for example between about 5 am and
about 11 am, and 1 or 2 capsules, each containing about 1 g of a
composition as described herein, are administered to the subject in
the evening, for example between about 5 pm and about 11 pm.
In some embodiments, the risk of a cardiovascular event in a
subject is reduced compared to a control population. In some
embodiments, a plurality of control subjects to a control
population, wherein each control subject is on stable statin
therapy, has a fasting baseline triglyceride level of about 135
mg/dL to about 500 mg/dL, and has established cardiovascular
disease or a high risk of developing cardiovascular disease, and
wherein the control subjects are not administered the composition
comprising about 1 g to about 4 g of eicosapentaenoic acid ethyl
ester per day.
In some embodiments, the risk of a cardiovascular event in a
subject is reduced compared to a control population. In some
embodiments, a plurality of control subjects to a control
population, wherein each control subject is on stable statin
therapy, has a fasting baseline triglyceride level of about 80
mg/dL to about 1500 mg/dL, and has established cardiovascular
disease or a high risk of developing cardiovascular disease, and
wherein the control subjects are not administered the composition
comprising about 1 g to about 4 g of eicosapentaenoic acid ethyl
ester per day.
In some embodiments, a first time interval beginning at (a) an
initial administration of a composition as disclosed herein to the
subject to (b) a first cardiovascular event of the subject is
greater than or substantially greater than a first control time
interval beginning at (a') initial administration of a placebo to
the control subjects to (b') a first cardiovascular event in the
control subjects. In some embodiments, the first cardiovascular
event of the subject is a major cardiovascular event selected from
the group consisting of: cardiovascular death, nonfatal myocardial
infarction, nonfatal stroke, coronary revascularization, and
unstable angina caused by myocardial ischemia. In some embodiments,
the first cardiovascular event of the control subjects is a major
cardiovascular event selected from the group consisting of:
cardiovascular death, nonfatal myocardial infarction, nonfatal
stroke, coronary revascularization, and unstable angina caused by
myocardial ischemia. In some embodiments, the first cardiovascular
event of the subject and the first cardiovascular event of the
control subjects is any of: death (from any cause), nonfatal
myocardial infarction, or nonfatal stroke. In some embodiments, the
first cardiovascular event of the subject and the first
cardiovascular event of the control subjects is any of: death from
a cardiovascular cause, nonfatal myocardial infarction, coronary
revascularization, unstable angina, peripheral cardiovascular
disease, or cardiac arrhythmia requiring hospitalization. In some
embodiments, the first cardiovascular event of the subject and the
first cardiovascular event of the control subjects is any of: death
from a cardiovascular cause, nonfatal myocardial infarction, and
coronary revascularization, unstable angina. In some embodiments,
the first cardiovascular event of the subject and the first
cardiovascular event of the control subjects is any of: death from
a cardiovascular cause and nonfatal myocardial infarction. In some
embodiments, the first cardiovascular event of the subject and the
first cardiovascular event of the control subjects is death (from
any cause). In some embodiments, the first cardiovascular event of
the subject and the first cardiovascular event of the control
subjects is any of: fatal myocardial infarction and nonfatal
myocardial infarction (optionally including silent MI). In some
embodiments, the first cardiovascular event of the subject and the
first cardiovascular event of the control subjects is coronary
revascularization. In some embodiments, the first cardiovascular
event of the subject and the first cardiovascular event of the
control subjects is hospitalization (e.g. emergent hospitalization)
for unstable angina (optionally unstable angina caused by
myocardial ischemia). In some embodiments, the first cardiovascular
event of the subject and the first cardiovascular event of the
control subjects is any one of: fatal stroke or nonfatal stroke. In
some embodiments, the first cardiovascular event of the subject and
the first cardiovascular event of the control subjects is any one
of: new coronary heart failure, new coronary heart failure leading
to hospitalization, transient ischemic attack, amputation for
coronary vascular disease, and carotid revascularization. In some
embodiments, the first cardiovascular event of the subject and the
first cardiovascular event of the control subjects is any one of:
elective coronary revascularization and emergent coronary
revascularization. In some embodiments, the first cardiovascular
event of the subject and the first cardiovascular event of the
control subjects is an onset of diabetes. In some embodiments, the
first cardiovascular event of the subject and the first
cardiovascular event of the control subjects is cardiac arrhythmia
requiring hospitalization. In some embodiments, the first
cardiovascular event of the subject and the first cardiovascular
event of the control subjects is cardiac arrest. In some
embodiments, the first cardiovascular event of the subject and the
first cardiovascular event of the control subjects is sudden
cardiac death and/or sudden death.
In some embodiments, a second time interval beginning at (a) an
initial administration of the composition to the subject to (c) a
second cardiovascular event of the subject is greater than or
substantially greater than a second control time interval beginning
at (a') initial administration of a placebo to the control subjects
to (c') a second cardiovascular event in the control subjects. In
some embodiments, the second cardiovascular event of the subject
and the second cardiovascular event of the control subjects is a
major cardiovascular event selected from the group consisting of:
cardiovascular death, nonfatal myocardial infarction, nonfatal
stroke, coronary revascularization, and unstable angina caused by
myocardial ischemia. In some embodiments, the major cardiovascular
event(s) is further selected from the group consisting of: cardiac
arrest, sudden cardiac death, and/or sudden death.
In some embodiments, the subject has diabetes mellitus and the
control subjects each have diabetes mellitus. In some embodiments,
the subject has metabolic syndrome and the control subjects each
have metabolic syndrome.
In some embodiments, the subject exhibits one or more of (a)
reduced triglyceride levels compared to the control population; (b)
reduced Apo B levels compared to the control population; (c)
increased HDL-C levels compared to the control population; (d) no
increase in LDL-C levels compared to the control population; (e) a
reduction in LDL-C levels compared to the control population; (f) a
reduction in non-HDL-C levels compared to the control population;
(g) a reduction in VLDL levels compared to the control population;
(h) a reduction in total cholesterol levels compared to the control
population; (i) a reduction in high sensitivity C-reactive protein
(hsCRP) levels compared to the control population; and/or (j) a
reduction in high sensitivity troponin (hsTnT) levels compared to
the control population.
In some embodiments, the subject's weight after administration of
the composition is less than a baseline weight determined before
administration of the composition. In some embodiments, the
subject's waist circumference after administration of the
composition is less than a baseline waist circumference determined
before administration of the composition.
In methods of the present disclosure in which a time interval is
determined or assessed, the time interval may be for example an
average, a median, or a mean time interval. For example, in
embodiments wherein a first control time interval is associated
with a plurality of control subjects, the first control time
interval is an average, a median, or a mean of a plurality of first
control time intervals associated with each control subject.
Similarly, in embodiments wherein a second control time interval is
associated with a plurality of control subjects, the second control
time interval is an average, a median, or a mean of a plurality of
second control time intervals associated with each control
subject.
In some embodiments, the reduced risk of cardiovascular events is
expressed as a difference in incident rates between a study group
and a control population. In some embodiments, the subjects in the
study group experience a first major cardiovascular event after an
initial administration of a composition as disclosed herein at a
first incidence rate which is less than a second incidence rate,
wherein the second incidence rate is associated with the rate of
cardiovascular events in the subjects in the control population. In
some embodiments, the first major cardiovascular event is any one
of: cardiovascular death, nonfatal myocardial infarction, nonfatal
stroke, coronary revascularization, and hospitalization for
unstable angina (optionally determined to be caused by myocardial
ischemia). In some embodiments, the first and second incidence
rates are determined for a time period beginning on the date of the
initial administration and ending about 4 months, about 1 year,
about 2 years, about 3 years, about 4 years, or about 5 years after
the date of initial administration.
In another embodiment, the disclosure provides use of any
composition described herein for treating hypertriglyceridemia in a
subject in need thereof, comprising: providing a subject having a
fasting baseline triglyceride level of about 135 mg/dL to about 500
mg/dL and administering to the subject a composition as described
herein. In one embodiment, the composition comprises about 1 g to
about 4 g of eicosapentaenoic acid ethyl ester, wherein the
composition contains substantially no docosahexaenoic acid.
In yet another embodiment, the disclosure provides use of any
composition described herein for treating hypertriglyceridemia in a
subject in need thereof, comprising: providing a subject having a
fasting baseline triglyceride level of about 80 mg/dL to about 1500
mg/dL and administering to the subject a composition as described
herein. In one embodiment, the composition comprises about 1 g to
about 4 g of eicosapentaenoic acid ethyl ester, wherein the
composition contains substantially no docosahexaenoic acid.
EXAMPLES
Example 1: Impact of Icosapent Ethyl on Reducing Cardiovascular
Events in High Risk Statin-Treated Patients
Among patients with cardiovascular risk factors who are receiving
treatment for secondary or primary prevention, the rates of
cardiovascular events remain high. Even in patients receiving
appropriate treatment with statins, a substantial residual
cardiovascular risk remains. In such patients, an elevated
triglyceride level serves as an independent marker for increased
ischemic risk, as shown in epidemiological and mendelian
randomization studies. In randomized trials, medications that
reduce triglycerides, such as extended-release niacin and fibrates,
have not reduced the rates of cardiovascular events when
administered in addition to appropriate medical therapy, including
statins. Further, contemporary trials and recent meta-analyses of
omega-3 fatty acid products have not shown benefit in patients
receiving statin therapy. Accordingly, the objective of the present
study was to determine if and how icosapent ethyl (referenced
interchangeably with AMR101 or VASCEPA.RTM.) reduced cardiovascular
events in patients with elevated triglyceride levels on a statin
therapy.
The following study, also referred to as the REDUCE-IT clinical
trial, was a large cardiovascular (CV) outcome trial designed to
assess CV risk reduction benefit of AMR101 treatment (commercially
known as VASCEPA.RTM.) versus placebo on the 5-point primary
composite endpoint: CV death, non-fatal stroke, non-fatal
myocardial infarction (MI), coronary revascularizations, or
unstable angina requiring hospitalization.
A multi-center, prospective, randomized, double-blind,
placebo-controlled, parallel-group study was performed to evaluate
the effect of AMR101 (4 g per day) on cardiovascular health and
mortality in hypertriglyceridemic patients with cardiovascular
disease or at high risk for cardiovascular disease. The intended
expanded indication of the study was treatment with AMR101 as an
add-on to statin therapy to reduce the risk of cardiovascular
events in patients with clinical cardiovascular disease or with
multiple risk factors for cardiovascular disease.
The primary objective of this study was, in patients at LDL-C goal
while on statin therapy, with established cardiovascular disease
(CVD) or at high risk for CVD, and hypertriglyceridemia (e.g.,
fasting triglycerides(TG) .gtoreq.200 mg/dL and <500 mg/dL), to
evaluate the effect of AMR101 4 g daily on time from randomization
to first occurrence of any component of the composite of the
following major CV events: CV death; nonfatal MI; (including silent
MI; electrocardiograms (ECGs) were performed annually for the
detection of silent MIs); nonfatal stroke; coronary
revascularization; and unstable angina determined to be caused by
myocardial ischemia by invasive/non-invasive testing and requiring
emergent hospitalization.
The key secondary objective of this study was to evaluate the
effect of AMR101 4 g daily on the time from randomization to the
first occurrence of the composite of following major CV events: CV
death, nonfatal MI (including silent MI), and nonfatal stroke.
Other secondary objectives for this study were to evaluate the
effect of therapy on time from randomization to the first
occurrence of the following individual or composite endpoints:
composite of CV death or nonfatal MI (including silent MI); fatal
or nonfatal MI (including silent MI); non-elective coronary
revascularization represented as the composite of emergent or
urgent classifications; CV death; unstable angina determined to be
caused by myocardial ischemia by invasive/non-invasive testing and
requiring emergent hospitalization; fatal or nonfatal stroke;
composite of total mortality, nonfatal MI (including silent MI), or
nonfatal stroke; and total mortality.
The key tertiary objectives for this study were to evaluate the
effect of AMR101 4 g daily from baseline and percent change form
baseline in fasting triglycerides and LDL-C. Other tertiary
objectives for this study were to evaluate the effect of therapy on
the following in addition to supporting efficacy and safety
analyses: Total CV events analysis defined as the time from
randomization to occurrence of the first and all recurrent major CV
events defined as CV death, nonfatal MI (including silent MI),
nonfatal stroke, coronary revascularization, or unstable angina
determined to be caused by myocardial ischemia by
invasive/non-invasive testing and requiring emergent
hospitalization; Primary composite endpoint in the subset of
patients with diabetes mellitus at baseline; Primary composite
endpoint in the subset of patients with metabolic syndrome at
baseline as defined with waist circumference of 35 inches (88 cm)
for all women and Asian, Hispanic, or Latino men, and .gtoreq.40
inches (102 cm) for all other men; Primary composite endpoint in
the subset of patients with impaired glucose metabolism at baseline
(Visit 2 fasting blood glucose (FBG) of 100-125 mg/dL); Key
secondary composite endpoint in the subset of patients with
impaired glucose metabolism at baseline (Visit 2 FBG 100-125
mg/dL); Composite of CV death, nonfatal MI (including silent MI),
nonfatal stroke, cardiac arrhythmia requiring hospitalization of 24
hours, or cardiac arrest; Composite of CV death, nonfatal MI
(including silent MI), non-elective coronary revascularizations
(defined as emergent or urgent classifications), or unstable angina
determined to be caused by myocardial ischemia by
invasive/non-invasive testing and requiring emergent
hospitalization; Composite of CV death, nonfatal MI (including
silent MI), non-elective coronary revascularizations (defined as
emergent or urgent classifications), unstable angina determined to
be caused by myocardial ischemia by invasive/non-invasive testing
and requiring emergent hospitalization, nonfatal stroke, or
peripheral vascular disease (PVD) requiring intervention, such as
angioplasty, bypass surgery, or aneurism repair; Composite of CV
death, nonfatal MI (including silent MI), non-elective coronary
revascularizations (defined as emergent or urgent classifications),
unstable angina determined to be caused by myocardial ischemia by
invasive/non-invasive testing and requiring emergent
hospitalization, PVD requiring intervention, or cardiac arrhythmia
requiring hospitalization of 24 hours; New congestive heart failure
(CHF); New CHF as the primary cause of hospitalization; Transient
ischemic attack (TIA); Amputation for PVD; Carotid
revascularization; All coronary revascularizations defined as the
composite of emergent, urgent, elective, or salvage; Emergent
coronary revascularizations; Urgent coronary revascularizations;
Elective coronary revascularizations; Salvage coronary
revascularizations; Cardiac arrhythmias requiring hospitalization
of .gtoreq.24 hours; Cardiac arrest; Ischemic stroke; Hemorrhagic
stroke; Fatal or nonfatal stroke in the subset of patients with a
history of stroke prior to baseline; New onset diabetes, defined as
Type 2 diabetes newly diagnosed during the treatment/follow-up
period; New onset hypertension, defined as blood pressure
.gtoreq.140 mmHg systolic or 90 mmHg diastolic newly diagnosed
during the treatment/follow-up period; Fasting triglycerides (TG),
total cholesterol (TC), low dense lipoprotein cholesterol (LDL-C),
high dense lipoprotein cholesterol (HDL-C), non-dense lipoprotein
cholesterol (non-HDL-C), very low dense lipoprotein cholesterol
(VLDL-C), apolipoprotein B (apo B), high sensitivity-C reactive
protein (hsCRP and log[hsCRP]), high-sensitivity troponin (hsTnT),
and remnant like particle cholesterol (RLP-C; were estimated from
standard lipid panel, RLP-C=TC-HDL-C-LDL-C [Varbo 2014]), (based on
ITT estimands): Assessment of the relationship between baseline
biomarker values and treatment effects within the primary and key
secondary endpoints; Assessment of the effect of AMR101 on each
marker: and Assessment of the relationship between post-baseline
biomarker values and treatment effects within the primary and key
secondary composite endpoints by including post-baseline biomarker
values (for example, at 4 months, or at 1 year) as a covariate.
Change from baseline and percent change from baseline in fasting
TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hsCRP, hsTnT, and
RLP-C; Change in body weight; and Change in waist circumference.
Study Population
The population for this study were men and women .gtoreq.45 years
of age with established CVD, or men and women .gtoreq.50 years of
age with diabetes in combination with one additional risk factor
for CVD. In addition, all patients had atherogenic dyslipidemia
defined as on treatment for hypercholesterolemia (but at treatment
goal for LDL-C, by treatment with a statin) and
hypertriglyceridemia. More details regarding the patient population
are listed in the inclusion criteria below. The patients needed to
provide consent to participate in the study and were willing and
able to comply with the protocol and the study procedures.
Study Periods
This study consisted of the following study periods:
Screening Period:
During the screening period, patients were evaluated for inclusion
and exclusion criteria.
At the first visit to the Research Unit (Visit 1), study procedures
were performed for evaluation of patient's eligibility in the
study. At this screening visit, patients signed an informed consent
form before any study procedure was performed; the informed consent
form covered the treatment/follow-up period. Based on the
evaluation from Visit 1, the following situations occurred:
Patients who were eligible for participation based on the study
procedures on Visit 1 returned to the Research Unit for Visit 2
(randomization visit) to start the treatment/follow-up period. This
case included, for example, patients at Visit 1 who were on a
stable dose of a statin, were planning to stay on the same statin
and the same dose of the statin, and who did not need to wash out
any non-statin lipid-altering medications. Patients who were not
eligible for participation based on the study procedures on Visit 1
and were unlikely to become eligible in the next 28 days (for
example: unlikely to stabilize statin dose, unable to wash out
non-statin lipid-altering medications, etc.): these patients were
screen failed after Visit 1. Patients that were not eligible for
participation in the study based on the study procedures on Visit 1
could become eligible in the next 28 days: To become eligible,
patients returned at the discretion of the investigator for a
second optional screening visit (Visit 1.1) at which time the
procedures needed for re-evaluation of the previously failed
inclusion/exclusion criteria were repeated. This case included, for
example, patients who were started on a statin at Visit 1, whose
statin dose was changed at Visit 1, and/or needed to wash out
non-statin lipid-altering medications. The following applied for
these patients: Patients with a change in the statin or statin dose
on Visit 1 needed to be on a stable statin dose for at least 28
days before the lipid qualifying measurements at Visit 1.1. Other
concomitant medications (antidiabetic therapy, for example) could
have been optimized or stabilized during this period. Patients
starting a washout at Visit 1 had a washout period of at least 28
days (only 7 days for bile acid sequestrants) before the lipid
qualifying measurements at Visit 1.1. Patients at Visit 1 who were
on a stable dose of a statin, were planning to stay on the same
statin at the same dose, and who did not need any medication
washout, but were asked to return for Visit 1.1 to repeat one or
more of the other study procedures not related to concomitant
medications. Patients who became eligible for participation based
on the additional study procedures at Visit 1.1 returned to the
Research Unit for Visit 2 (randomization visit) to start the
treatment/follow-up period.
At the end of the screening period, patients needed to meet all
inclusion and exclusion criteria before they were randomized.
Patients who were not eligible for participation after the
screening period (based on study procedures at Visit 1 and/or Visit
1.1) could return at a later date for rescreening. These patients
needed to re-start with all procedures starting with Visit 1. This
included patients who need more time to stabilize one or more
conditions or therapies (for example: statin, antidiabetic,
antihypertensive, thyroid hormone, HIV-protease inhibitor
therapy).
Treatment/Follow-Up Period: Within 42 days after the first
screening visit (Visit 1) or within 60 days after the first
screening visit (Visit 1) for those patients that had a second
screening visit (Visit 1.1), eligible patients entered the
treatment/follow-up period. During this period, the patients
received study drug during the planned visits at the Research Site
and took the study drug while away from the Research Site.
During the visits, study procedures were performed for evaluation
of efficacy and safety. A detailed schedule of the procedures is
provided below in Table 1.
TABLE-US-00001 TABLE 1 Schedule of Procedures Screening If a Visit
1.1 takes place, Visit 1 may Up to occur up to 42 days 60 days
Follow-Up (FU)[.sup.13] before before Last Visit Study Day Day 0
Day 0.sup.[2] 0 120 .+-. 10 360 .+-. 10 720 .+-. 10 1080 .+-. 10
1440 .+-. 10 1800 + 30 2160 .+-. 10 (LV).sup.[15] Months of FU 0 4
12 24 36 48 60 72 Varies Years of FU 0 0.33 1 2 3 4 5 6 Varies
Visit # 1 1.1 2 3 4 5 6 7 8 9.sup.[14] LV Study Procedures:
Informed X Consent Medical, X Surgical & Family History
Demographics X Evaluate X.sup.[1] X.sup.[3] X inclusion/ exclusion
criteria Physical X X X X X X X X X Examination Weight, X X X X X X
X X X X Height.sup.[4] Vital Signs.sup.[5] X X X X X X X X X X X
Waist X X X Circumference 12-Lead ECG X X X X X X X X X Urine X X
pregnancy test.sup.[6] Concomitant X X X X X X X X X X X Meds
Randomization X Dosing X X X X X X X X at the Research Site.sup.[7]
Efficacy events X X X X X X X X AE Evaluations X X X X X X X X X
Compliance X X X X X X X X Check.sup.[8] Chemistry and X .sup.
X.sup.3 X X X X X X X X X hematology.sup.[9] Fasting lipid X .sup.
X.sup.3 X X X X X X X X X profile.sup.[10] Genetic X
testing.sup.[11] Biomarkers: X X X hsCRP, apo B, hsTNT Fasting
blood X X X X X X X X sample for archiving .sup.[12]
.sup.[1]Includes procedures and (fasting) blood samples (for
example, hsCRP, calculated creatinine clearance) as needed to
determine the CV risk category (see inclusion criteria).
.sup.[2]Screening visit to re-evaluate inclusion/exclusion criteria
for patients who were not eligible for participation based on data
from Visit 1. .sup.[3]Inclusion/exclusion criteria were
re-evaluated for selected study procedures that were performed on
Visit 1.1 because patients failed to meet them at Visit 1.
.sup.[4]Height at first screening visit only. .sup.[5]Vital signs,
including systolic and diastolic blood pressure (mmHg), heart rate,
respiratory rate and body temperature. Participants were seated for
at least 5 minutes before assessments of vital signs. .sup.[6]For
women of childbearing potential. .sup.[7]The patients fasted at
least 10 hours before arriving at the Research Site, when all
fasting blood samples were obtained. After blood samples were
obtained, patients were given drug with food. .sup.[8]Review study
drug compliance by unused capsule count, discussed with and
counseled patients about compliance if needed; final study
compliance at last visit. .sup.[9]Safety Laboratories - Complete
Blood Count: Included RBC, Hgb, Hct, WBC and differential, and
platelet count. Biochemistry includes total protein, albumin,
alkaline phosphatase, ALT, AST, total bilirubin, glucose, calcium,
electrolytes (sodium, potassium, chloride), blood urea nitrogen
(BUN), serum creatinine, uric acid, creatine kinase, HbA1c. Safety
labs were repeated as deemed necessary by the Investigator.
.sup.[10]TG, TC, HDL-C, LDL-C, non-HDL-C, and VLDL-C.
.sup.[11]Fasting blood sample were stored for future genetic
testing at the discretion of the Sponsor. This sample was optional
as local regulations may prohibit genetic samples to be collected
or shipped outside the country, or patients may not have consented.
.sup.[12] Used at the Sponsor's discretion to perform repeat
analyses described in the protocol or to perform other tests
related to cardiovascular health. [.sup.13]Site personnel contacted
each patient by telephone in-between Visit 2 and Visit 3 and
between Visit 3 and Visit 4. After Visit 4 contact was made every 3
months. The purpose of the contact was to collect information about
efficacy events, adverse events, concomitant medications, confirm
patient's current address and contact information and remind
patients about taking their study medication and logistics for the
next visit. .sup.[14]Office visits continued at 360-day intervals
and phone visits at 90-day intervals until study end date was
determined. .sup.[15]The last visit (LV) could have occurred within
30 days after the study end date as determined by the DMC; the
study end date is tentatively schedule for Day 2160 but the actual
date was determined by the DMC may be different.
Study Duration
Patients were randomized at different times during the enrollment
period but all ended the study at approximately the same date
(i.e., at the study end date) and, therefore, the duration of
follow-up differed based on date of randomization. It was planned
that all randomized patients received study medication and were
followed-up until the study end date. It was expected that a
minimum of approximately 1612 primary endpoint events were required
during the study. 8179 patients were randomized at multiple
Research Sites worldwide over a period of approximately 4.2 years.
After randomization, patients were treated and followed up to an
estimated maximum of 6.5 years. The study end date was determined
to be when approximately 1612 primary efficacy events had been
adjudicated. Table 2 shows the study milestones from the first
patient screened to the last patient visit and subsequent database
lock.
TABLE-US-00002 TABLE 2 Study Milestones Study Milestones Date First
Patient Screened 21 Nov. 2011 First Patient Randomized 28 Nov. 2011
Last Patient Randomized 4 Aug. 2016 SAP Finalization 8 Jul. 2016
First DMC Interim Efficacy Review 9 Sep. 2016 Second DMC Interim
Efficacy Review 11 Aug. 2017 First Patient Last Visit 1 Mar. 2018
Last Patient Last Visit 31 May 2018 Database Lock 6 Sep. 2018
Study Groups
At Visit 2 (Day 0), eligible study patients were randomly assigned
to the following treatment groups: Group 1: AMR101 (>96% E-EPA)
4 g daily (four 1000 mg capsules daily) Group 2: placebo (four
capsules daily)
The four AMR101 or placebo capsules daily were taken as two
capsules in the morning and two capsules in the evening
(twice-per-day dosing regimen).
Number of Patients
This was an event-driven trial and it was expected that a minimum
of 1612 primary efficacy endpoint events were required during the
study. A total of approximately 8179 patients entered into the
study to either receive AMR101 or placebo (approximately 4089
patients per treatment group) in order to observe an estimated 1612
events that made up the primary composite endpoint for
efficacy.
Randomization
On Day 0, eligible patients were randomized to one of the 2 study
groups using a computer-generated randomization schema. Randomized
treatment assignment to either AMR101 or placebo in a 1:1 ratio was
provided using the internet (lWR).
Blinding
This was a double-blind study. Patients, investigators, pharmacists
and other supporting staff at the Research Sites, personnel and
designees of the Sponsor, study administrators and personnel at the
organization(s) and vendors supporting the study were unaware of
the randomization code (i.e., they did not know which study
participants were receiving the experimental drug and which were
receiving the placebo drug). The study medication AMR101 and
placebo capsules were similar in size and appearance to maintain
blinding.
During the double-blind treatment/follow-up period, everyone
(patients, investigators, pharmacists and other supporting staff at
the Research Sites, personnel and designees of the Sponsor, study
administrators and personnel at the organization(s) and vendors
managing/supporting the study), with the exception of the
laboratory personnel performing the analysis, were blinded to
individual results of the efficacy laboratory measurements
(including lipid values). Individual results from the lipid profile
could be unblinded in the event of an emergency for a patient.
Stratification
Participants were assigned to treatment groups stratified by CV
risk category, use of ezetimibe and by geographical region (e.g.,
Westernized, Eastern European, and Asia Pacific countries). There
were two CV risk categories: CV Risk Category 1: patients with
established CVD defined in the inclusion criteria. Patients with
diabetes and established CVD were included in this category. These
patients are defined as the secondary prevention stratum, primary
risk category, and/or secondary prevention cohort. CV Risk Category
2: patients with diabetes and at least one additional risk factor
for CVD, but no established CVD. These patients are defined as the
primary prevention stratum, secondary risk category, and/or primary
prevention cohort.
Stratification was recorded in the IWR at the time of enrollment.
Approximately 70% of randomized patients were in the CV Risk
Category 1 and approximately 30% of randomized patients were in the
CV Risk Category 2. Enrollment with patients of a CV risk category
was stopped when the planned number of patients in that risk
category was reached.
Study Population
Inclusion Criteria.
A detailed list of the inclusion criteria for this study is
provided in Tables 3-5. Specifically, Table 3 outlines the
inclusion criteria for patients in this study whereas Tables 4 and
5 further outline the inclusion criteria based on whether that
patient is part of the primary prevention risk category or the
secondary prevention risk category of patients, respectively.
TABLE-US-00003 TABLE 3 Patient Inclusion Criteria for this Study
Study Inclusion Criteria 1 Men or women .gtoreq.45 years of age
with established CVD (i.e., Primary Prevention Risk Category; see
Table 4) or .gtoreq.50 years of age with diabetes in combination
with one additional risk factor for CVD (i.e., Secondary Prevention
Risk Category; see Table 5). 2 Fasting TG levels .gtoreq.150 mg/dL
(2.26 mmol/L) and <500 mg/dL (5.64 mmol/L). Due to the
variability of triglycerides, a 10% allowance existed in the
initial protocol, which permitted patients to be enrolled with
qualifying triglyceride levels .gtoreq.135 mg/dL. Protocol
amendment made in May of 2013 changed the lower limit of acceptable
triglyceride levels from 150 mg/dL to 200 mg/dL, with no
variability allowance. 3 LDL-C >40 mg/dL and .ltoreq.100 mg/dL
and on stable statin therapy (.+-. ezetimibe) for .gtoreq.4 weeks
prior to the LDL-C and TG qualifying measurements for
randomization. 4 Women who are not pregnant, not breastfeeding, not
planning on becoming pregnant, and using an acceptable form of
birth control during the study (if of child-bearing potential),
unless their sexual partner(s) were surgically sterile or the woman
was abstinent. Women of child bearing potential needed a negative
urine pregnancy test prior to randomization. 5 Able to provide
informed consent and adhere to study schedules. 6 Agree to follow
and maintain a physician-recommended diet during the study.
Stable therapy was defined as the same daily dose of the same
statin for at least 28 days before the lipid qualification
measurements (TG and LDL-C) and, if applicable, the same daily dose
of ezetimibe for at least 28 days before the lipid qualification
measurements (TG and LDL-C). Patients who had their statin therapy
or use of ezetimibe initiated at Visit 1, or had their statin,
statin dose and/or ezetimibe dose changed at Visit 1, needed to go
through a stabilization period of at least 28 days since
initiation/change and had their qualifying lipid measurements
measured (TG and LDL-C) after the washout period (at Visit 1.1).
Statins may have been administered with or without ezetimibe.
If patients qualified at the first qualification visit (Visit 1)
for TG and LDL-C, and met all other inclusion/exclusion criteria,
they were randomized at Visit 2. If patients did not qualify at the
first qualifying visit (Visit 1), a second re-qualifying visit
(Visit 1.1) was allowed. For some patients, because they needed to
stabilize medications and/or needed to washout medications, the
second re-qualifying visit (Visit 1.1) was needed after the
stabilization/washout period.
Women were not considered to be of childbearing potential if they
met one of the following criteria as documented by the
investigator: they had a hysterectomy, tubal ligation or bilateral
oophorectomy prior to signing the informed consent form; and/or
they were post-menopausal, defined as .gtoreq.1 year since their
last menstrual period or have a follicle-stimulating hormone (FSH)
level in a menopausal range.
Patients having established CVD (in CV Risk Category 1) were
defined as detailed in Table 4.
TABLE-US-00004 TABLE 4 Inclusion Criteria for the Primary
Prevention Risk Category (i.e., CV Risk Category 1) Primary
Prevention Risk Category (i.e., Secondary Prevention Cohort)
Defined as men and women .gtoreq.45 years of age with one or more
of the following: 1 Documented coronary artery disease (CAD; one or
more of the following primary criteria must be satisfied): a.
Documented multi vessel CAD (.gtoreq.50% stenosis in at least two
major epicardial coronary arteries-- with or without antecedent
revascularization). b. Documented prior MI. c. Hospitalization for
high-risk non-ST-segment elevation acute coronary syndrome
(NSTE-ACS) (with objective evidence of ischemia: ST-segment
deviation or biomarker positivity). 2 Documented cerebrovascular or
carotid disease (one of the following primary criteria must be
satisfied): a. Documented prior ischemic stroke. b. Symptomatic
carotid artery disease with .gtoreq.50% carotid arterial stenosis.
c. Asymptomatic carotid artery disease with .gtoreq.70% carotid
arterial stenosis per angiography or duplex ultrasound. d. History
of carotid revascularization (catheter-based or surgical). 3
Documented peripheral arterial disease (PAD; one or more of the
following primary criteria must be satisfied): a. Ankle-brachial
index (ABI) <0.9 with symptoms of intermittent claudication. b.
History of aorto-iliac or peripheral arterial intervention
(catheter-based or surgical).
Patients at high risk for CVD (in CV Risk Category 2) were defined
as detailed in Table 5.
TABLE-US-00005 TABLE 5 Inclusion Criteria for the Secondary
Prevention Risk Category (i.e., CV Risk Category 2) Secondary
Prevention Risk Category (i.e., Primary Prevention Cohort) Defined
as having each of the following: 1 Diabetes mellitus (Type 1 or
Type 2) requiring treatment with medication. 2 Men and women
.gtoreq.50 years of age. 3 One of the following at Visit 1
(additional risk factor for CVD): a. Men .gtoreq.55 years of age
and Women .gtoreq.65 years of age. b. Cigarette smoker or stopped
smoking within 3 months before Visit 1. c. Hypertension (blood
pressure .gtoreq.140 mmHg systolic OR .gtoreq.90 mmHg diastolic) or
on antihypertensive medication. d. HDL-C .ltoreq.40 mg/dL for men
or .ltoreq.50 mg/dL for women. e. HsCRP >3.00 mg/L (0.3 mg/dL).
f. Renal dysfunction: Creatinine clearance (CrCL) >30 and <60
mL/min. g. Retinopathy, defined as any of the following:
non-proliferative retinopathy, pre-proliferative retinopathy,
proliferative retinopathy, maculopathy, advanced diabetic eye
disease or a history of photocoagulation. h. Micro- or
macroalbuminuria. Microalbuminuria is defined as either a positive
micral or other strip test (may be obtained from medical records),
an albumin/creatinine ratio .gtoreq.2.5 mg/mmol or an albumin
excretion rate on timed collection .gtoreq.20 mg/min all on at
least two successive occasions; macroalbuminuria, defined as
Albustix or other dipstick evidence of gross proteinuria, an
albumin/creatinine ratio .gtoreq.25 mg/mmol or an albumin excretion
rate on timed collection .gtoreq.200 mg/min all on at least two
successive occasions. i. ABI <0.9 without symptoms of
intermittent claudication (patients with ABI <0.9 with symptoms
of intermittent claudication are counted under Secondary Prevention
Risk Category). Patients with diabetes and CVD as defined above are
eligible based on the CVD requirements and will be counted under CV
Risk Stratum 1. Only patients with diabetes and no documented CVD
as defined above needed at least one additional risk factor as
listed, and were counted under Primary Prevention Risk
Category.
Exclusion Criteria:
Patients meeting the following exclusion criteria enumerated in
Table 6 were not eligible for the study.
TABLE-US-00006 TABLE 6 Patient Exclusion Criteria for this Study
Study Exclusion Criteria 1 Severe (New York Heart Association
[NYHA] class IV) heart failure. 2 Any life-threatening disease
expected to result in death within the next 2 years (other than
CVD). 3 Diagnosis or laboratory evidence of active severe liver
disease. 4 Hemoglobin A1c >10.0% (or 86 mmol/mol IFCC units) at
screening (Visit 1). If patients failed this criterion (HbA1c
>10.0% or 86 mmol/mol IFCC units) at Visit 1, they could have
had their antidiabetic therapy optimized and be retested at Visit
1.1. 5 Poorly controlled hypertension: systolic blood pressure
(SBP) .gtoreq.200 mmHg or diastolic blood pressure (DBP)
.gtoreq.100 mmHg (despite antihypertensive therapy). 6 Planned
coronary intervention or any non-cardiac major surgical procedure.
7 Known familial lipoprotein lipase deficiency (Fredrickson Type
I), apolipoprotein C-II deficiency, or familial
dysbetalipoproteinemia (Fredrickson Type III). 8 Participation in
another clinical trial involving an investigational agent within 90
days prior to screening (Visit 1). Patients could not participate
in any other investigational medication or medical device trial
while participating in this study (participation in a registry or
observational study without an additional therapeutic intervention
was allowed). 9 Intolerance or hypersensitivity to statin therapy.
10 Known hypersensitivity to fish and/or shellfish, or ingredients
of the study product or placebo. 11 History of acute or chronic
pancreatitis. 12 Malabsorption syndrome and/or chronic diarrhea.
(Note: patients who had undergone gastric/intestinal bypass surgery
were considered to have malabsorption, hence were excluded;
patients who had undergone gastric banding were allowed to enter
the trial). 13 Use of non-study drug-related, non-statin,
lipid-altering medications, dietary supplements, or foods during
the screening period (after Visit 1) and/or plans for use during
the treatment/follow-up period including: a. niacin >200 mg/day
or fibrates during the screening period (after Visit 1) and/or
planned to use during the study; patients who were taking niacin
>200 mg/day or fibrates during the last 28 days before Visit 1
needed to go through washout of at least 28 days after their last
use and have their qualifying lipids measured (TG and LDL-C) after
the washout period (Visit 1.1). b. any omega-3 fatty acid
medications (prescription medicines containing EPA and/or DHA)
during the screening period (after Visit 1) and/or planned to use
during the treatment/follow-up period of the study. To be eligible
for participation in the study, patients who were taking omega-3
fatty acid medications during the last 28 days before Visit 1
(except patients in The Netherlands), needed to go through a
washout period of at least 28 days after their last use and have
their qualifying lipids measured (TG and LDL-C) after the washout
period (at Visit 1.1). However, for patients in the Netherlands
only being treated with omega-3 fatty acid medications containing
EPA and/or DHA were excluded and no washout was allowed. c. dietary
supplements containing omega-3 fatty acids (e.g., flaxseed, fish,
krill, or algal oils) during the screening period (after Visit 1)
and/or planned to use during the treatment/follow-up period of the
study. To be eligible for participation in the study, patients who
were taking >300 mg/day omega-3 fatty acids (combined amount of
EPA and DHA) within 28 days before Visit 1 (except patients in The
Netherlands), needed to go through a washout period of at least 28
days since their last use and have their qualifying lipid
measurements measured (TG and LDL-C) after the washout period (at
Visit 1.1). However, for patients in the Netherlands only being
treated with dietary supplements containing omega-3 fatty acids of
>300 mg/day EPA and/or DHA were excluded and no washout was
allowed. d. bile acid sequestrants during the screening period
(after Visit 1) and/or planned to use during the
treatment/follow-up period of the study. To be eligible for
participation in the study, patients who were taking bile acid
sequestrants within 7 days before Visit 1, needed to go through a
washout period of at least 7 days since their last use and have
their qualifying lipid measurements measured (TG and LDL-C) after
the washout period (at Visit 1.1). e. proprotein convertase
subtilisin kexin 9 (PCSK9) inhibitors during the screening period
(after Visit 1) and/or planned to use during the
treatment/follow-up period of the study. To be eligible for
participation in the study, patients could not have taken a PCSK9
inhibitor within 90 days prior to their screening visit. 14 Other
medications (not indicated for lipid alteration): a. Tamoxifen,
estrogens, progestins, thyroid hormone therapy, systemic
corticosteroids (local, topical, inhalation, or nasal
corticosteroids are allowed), HIV-protease inhibitors that have not
been stable for .gtoreq.28 days prior to the qualifying lipid
measurements (TG and LDL-C) during screening. To be eligible for
participation in the study, patients who were not taking a stable
dose of these medications within 28 days before Visit 1, needed to
go through a stabilization period of at least 28 days since their
last dose change and have their qualifying lipid measurements
measured (TG and LDL-C) after the washout period (at Visit 1.1). b.
Cyclophosphamide or systemic retinoids during the screening period
(unless .gtoreq.28 day washout) and/or plans for use during the
treatment/follow-up period. To be eligible for participation in the
study, patients who were taking these medications within 28 days
before Visit 1, needed to go through a washout period of at least
28 days since their last use and have their qualifying lipid
measurements measured (TG and LDL-C) after the washout period (at
Visit 1.1). 15 Known AIDS (HIV-positive patients without AIDS are
allowed). 16 Requirement for peritoneal dialysis or hemodialysis
for renal insufficiency or creatinine clearance <30 mL/min (0.50
mL/sec). 17 Unexplained elevated creatine kinase concentration
>5 .times. ULN or elevation due to known muscle disease (e.g.,
polymyositis, mitochondrial dysfunction) at Visit 1. 18 Any
condition or therapy which, in the opinion of the investigator,
might pose a risk to the patient or make participation in the study
not in the patient's best interest. 19 Drug or alcohol abuse within
the past 6 months, and inability/unwillingness to abstain from drug
abuse and excessive alcohol consumption during the study or
drinking 5 units or more for men or 4 units or more for women in
any one hour (episodic excessive drinking or binge drinking).
Excessive alcohol consumption was on average >2 units of alcohol
per day. A unit of alcohol was defined as a 12-ounce (350 mL) beer,
5-ounce (150 mL) wine, or 1.5-ounce (45 mL) of 80-proof alcohol for
drinks. 20 Mental/psychological impairment or any other reason to
expect patient difficulty in complying with the requirements of the
study or understanding the goal and potential risks of
participating in the study (evaluated at Visit 1).
Study Procedures
The Screening Period for this study included two visits, Visit 1
and Visit 1.1.
Screening Visit (Visit 1):
During Visit 1, patients came to the Research Site for and were
instructed to fast for at least 10 hours before their visit. If
patients qualified for randomization based on the procedures at
Visit 1, they needed to be randomized within 42 days after Visit 1.
The following procedures were performed at the screening Visit 1:
Obtained signed informed consent; Assigned the patient a patient
number; Obtained medical, surgical and family history; Recorded
demographics; Obtained height, weight, and body mass index;
Obtained vital signs (systolic and diastolic blood pressure, heart
rate, respiratory rate, and body temperature); Obtained a 12-lead
electrocardiogram; Evaluated inclusion/exclusion criteria, This
included procedures and (fasting) blood samples (for example,
hsCRP, calculated creatinine clearance) as needed to determine the
CV risk category (See inclusion criteria); Obtained fasting blood
samples for chemistry and hematology testing; Obtained a fasting
blood sample for the lipid profile (TG, TC, HDL-C, LDL-C,
non-HDL-C, VLDL-C); Performed a urine pregnancy test on women of
childbearing potential; Recorded concomitant medication(s); and
Instructed patient to fast for at least 10 hours prior to the next
visit.
Screening Visit (Visit 1.1):
Patients who qualified for study participation after Visit 1
because they meet all inclusion criterion and none of the exclusion
criteria, skipped Visit 1.1 and returned to the Research Site for
Visit 2 to be randomized and to start the treatment/follow-up
period of the study. For these patients, Visit 2 occurred soon
after Visit 1. Patients, who did not qualify at Visit 1, returned
to the Research Site for a second qualifying visit (Visit 1.1) at
the discretion of the investigator. At Visit 1.1, procedures that
caused failure of eligibility at Visit 1 were repeated. Patients
were eligible for randomization after Visit 1.1 if they meet all
inclusion criteria and if they no longer failed the exclusion
criteria. If patients were evaluated at Visit 1.1 and qualified for
randomization based on the repeated procedures at Visit 1.1, they
needed to be randomized within 60 days after Visit 1. For some
patients, Visit 1.1 was mandatory at least 28 days after Visit 1 in
order to check eligibility. These were patients who at Visit 1
started treatment with a statin, changed their statin, changed the
daily dose of their statin, started to washout prohibited
medications or started a stabilization period with certain
medications (See inclusion/exclusion criteria above for details).
Any of these changes at Visit 1 may have affected the qualifying
lipid levels and therefore, patients needed to have Visit 1.1 to
determine whether they qualified based on lipid level requirements
(TG and LDL-C) determined at Visit 1. Other procedures that caused
failure of eligibility at Visit 1 were also repeated at Visit 1.1.
The following procedures were performed at the screening Visit 1.1:
Obtained vital signs (systolic and diastolic blood pressure, heart
rate, respiratory rate, and body temperature); Evaluated
inclusion/exclusion criteria; only those evaluations were repeated
that deemed the patient not eligible on Visit 1; Obtained fasting
blood samples for chemistry and hematology testing. Only those
samples were obtained that deemed the patient not eligible on Visit
1; Obtained a fasting blood sample for the lipid profile (TG, TC,
HDL-C, LDL-C, non-HDL-C, VLDL-C) if the patient was deemed not
eligible on Visit 1. This included patients who at Visit 1 started
treatment with a statin, changed their statin, changed the daily
dose of their statin, started to washout prohibited medications or
started a stabilization period with certain medications (See
inclusion/exclusion criteria for details). These patients had a
fasting blood sample collected at Visit 1.1 for the qualifying
lipid values (TG and LDL-C), and the TG and LDL-C inclusion
criteria were evaluated and Recorded concomitant medication(s).
The treatment/follow-up period for this study included Visit 2,
Visit 3, and Visits 4-9. Every attempt was made to complete the
follow-up visits during the defined window periods.
Randomization Visit (Visit 2; Day 0):
Qualified patients returned to the Research Site for Visit 2. The
following procedures were performed at Visit 2: Performed physical
examination; Obtained weight; Obtained vital signs (systolic and
diastolic blood pressure, heart rate, respiratory rate, and body
temperature); Measured waist circumference (one of the factors to
diagnose metabolic syndrome); Obtained a 12-lead electrocardiogram;
Evaluated inclusion/exclusion criteria; Obtained fasting blood
samples for: Chemistry and hematology testing; Lipid profile
(baseline); Biomarker assays (baseline); Genetic testing (optional
blood sample); and Archived (in countries and at sites approved by
IRB/IEC and dependent on country regulations). Performed a urine
pregnancy test on women of childbearing potential (must be negative
for randomization); Dispensed study drug and record randomization
number; Instructed patient on how to take study drug; Administered
study drug--Note: Study drug was taken orally with food following
the collection of all fasting blood samples; Assessed for and
recorded adverse events; Recorded concomitant medication(s); and
Instructed patient: To bring all study supplies with them to the
next visit; Not to take study drug on the morning of their next
visit; and To fast for .gtoreq.10 hours prior to the next
visit.
Visit 3 (Day 120; .about.4 Months):
Patients returned to the Research Site for Visit 3 on Day 120.+-.10
days. The following procedures were performed: Physical
examination; Obtained weight; Obtained vital signs (systolic and
diastolic blood pressure, heart rate, respiratory rate, and body
temperature); Obtained fasting blood samples for: Chemistry and
hematology testing; and Lipid profile. Reviewed study drug
compliance by unused capsule count; discuss with and counsel
patients about compliance if needed; Administered study drug--Note:
Study drug should be taken orally with food following the
collection of all fasting blood samples; Assessed and record
efficacy events; Assessed for and record adverse events; Recorded
concomitant medication(s); Instructed patient: To bring all study
supplies with them to the next visit; Not to take study drug on the
morning of their next visit; and To fast for 10 hours prior to the
next visit.
Visits 4, 5, 6, 7, 8, and 9:
At Visit 4: Day 360.+-.10; Visit 5: Day 720.+-.10; Visit 6: Day
1080.+-.10; and Visit 7: Day 1440.+-.10: Visit 8: Day 1800.+-.10,
Visit 9: Day 2160.+-.10, the following procedures were performed:
Physical examination; Obtained weight; Obtained vital signs
(systolic and diastolic blood pressure, heart rate, respiratory
rate, and body temperature); Measured waist circumference
(collected at Visit 5 only); Obtained a 12-lead electrocardiogram;
Obtained fasting blood samples for: Chemistry and hematology
testing; Lipid profile; Biomarker assays (collected at Visit 5
only); and Archived (in countries and at sites approved by
international review board (IRB)/independent ethics committee (IEC)
and dependent on country regulations); Reviewed study drug
compliance by unused capsule count; discussed with and counseled
patients about compliance if needed; Administered study drug--Note:
Study drug should be taken orally with food following the
collection of all fasting blood samples; Assessed and record
efficacy events; Assessed for and record adverse events; Recorded
concomitant medication(s); and Instructed patient: To bring all
study supplies with them to the next visit; Not to take study drug
on the morning of their next visit; and To fast for .gtoreq.10
hours prior to the next visit.
Additional Visits:
The end date of the study was expected for Day 2160 but the actual
end date was dependent on the determination of the study end date
by the DMC and when approximately 1612 primary efficacy events had
occurred. If the actual study end date was later than the expected
end date, additional visits were planned between Visit 7 and the
Last Visit with a maximum of 360.+-.10 days between visits. If the
actual study end date was sooner than the expected end date, fewer
visits occurred, and the last visit (See below, section titled Last
Visit--End of Study) occurred sooner. On additional visits the same
procedures were performed. Irrespective of the number of additional
visits, after the DMC had established the end of the study date,
there was a last visit with procedures as listed below in section
titled Last Visit--End of Study.
Last Visit--End of Study:
All patients completed the study at the same time (within a 30-day
window after the study end date), irrespective of the date that
they were randomized. The end date of the study was planned for Day
2160 but the actual end date was dependent on the determination of
the study end date by the DMC when approximately 1612 primary
efficacy events had occurred (event-driven trial). For each
patient, the last visit may have occurred within 30 days after the
actual study end date as determined by the DMC. However, for the
efficacy endpoints based on CV events, only events occurring up to
and including the scheduled actual study end date were included in
the efficacy analyses. A final follow-up visit was required for all
patients. In a rare case that a final follow-up visit did not occur
within the 30-day timeframe following the study end date, any
attempt to contact the patient was recorded on a special contact
form, until/unless appropriate information was obtained. At the
Last Visit, the following procedures were performed: Physical
examination; Obtained weight; Obtained vital signs (systolic and
diastolic blood pressure, heart rate, respiratory rate, and body
temperature); Measured waist circumference; Obtained a 12-lead
electrocardiogram Obtained fasting blood samples for: Chemistry and
hematology testing; Lipid profile; Biomarker assays; and Archived
(in countries and at sites approved by IRB/IEC and dependent on
country regulations). Determined study drug compliance by unused
capsule count; Assessed and record efficacy events; Assessed for
and record adverse events; and Recorded concomitant
medication(s).
Telephoned Follow-Up Contact:
Site personnel contacted each patient by telephone on the following
study days: Day 60.+-.3 days; Day 180.+-.5 days; Day 270.+-.5 days;
Day 450.+-.5 days; Day 540.+-.5 days; Day 630.+-.5 days; Day
810.+-.5 days; Day 900.+-.5 days; Day 990.+-.5 days; Day 1170.+-.5
days; Day 1260.+-.5 days; Day 1350.+-.5 days; Day 1530.+-.5 days;
Day 1620.+-.5 days; Day 1710.+-.5 days; Day 1890.+-.5 days; Day
1980.+-.5 days; and Day 2070.+-.5 days.
If the treatment/follow-up period of the study was extended beyond
the expected end date (Day 2160), additional follow-up phone calls
were made every 3 months in-between additional visits .+-.5 days.
If the treatment/follow period of the study was shorter than the
expected end date, less follow-up phone calls were needed. Every
attempt was made to talk to each patient within this timeframe. The
following information was collected from the patient: Possible
efficacy endpoints related to CV events. Patients were asked to
return to the Research Site to assess for any endpoints or events
identified; Adverse events; Concomitant medications; and Current
address and contact information.
Patients were reminded about the following items: To take the study
medication according to the dosing schedule assigned, with food;
When to return to the Research Center for the next visit; To bring
the unused study medication to the next visit; To not take study
drug on the morning of their next visit; and To fast for at least
10 hours prior to the next visit. Laboratory Procedures
Clinical Laboratory Procedures and Evaluations:
All clinical laboratory determinations for screening and safety
were performed by a certified clinical laboratory under the
supervision of the Sponsor or its designee. Whenever possible and
appropriate, samples for the clinical laboratory procedures were
collected after fasting for at least 10 hours. For the purposes of
this study, fasting was defined as nothing by mouth except water
(and any essential medications). The investigator reviewed and
signed all laboratory test reports. At screening, patients who had
laboratory values that are outside the exclusionary limits
specified in the exclusion criteria were not enrolled in the study
(patients would have been considered for the study if values were
classified as not clinically significant by the investigator).
After randomization, the investigator was notified if laboratory
values were outside of their normal range. In this case, the
investigator was required to conduct clinically appropriate
follow-up procedures.
Safety Laboratory Tests:
The safety parameters were analyzed by a certified clinical
laboratory at screening (Visit 1 or Visit 1.1), Randomization visit
(Visit 2; Day 0), Visit 3 (Day 120; .about.4 Months) and all other
follow-up visits including the Last Visit. The safety laboratory
tests included: Hematology with complete blood count (CBC),
including RBC, hemoglobin (Hgb), hematocrit (Hct), white cell blood
count (WBC), white cell differential, and platelet count; and
Biochemistry panel including total protein, albumin, alkaline
phosphatase, alanine aminotransferase (ALT/SGPT), aspartate
aminotransferase (AST/SGOT), total bilirubin, glucose, calcium,
electrolytes (sodium, potassium, chloride), blood urea nitrogen
(BUN), serum creatinine, uric acid, creatine kinase, and
=HbA1c.
Each laboratory result was classified as low (L), normal (N), and
high (H) at each visit according to the laboratory-supplied normal
range. The shift from baseline was presented for each post-baseline
visit and overall post-baseline visits. If multiple measurements
for a test parameter were available for a post-baseline
patient-visit, the most extreme value was included in the shift
table. For shift from baseline to overall post-baseline visits,
values from all visits (including unscheduled measurements) were
included. The chemistry shift table included fasting lipid
parameters. The continuous lipid values were presented as part of
the efficacy analysis.
Fasting Lipid Profile:
The fasting lipid panel included: TG, TC, LDL-C, HDL-C, non-HDL-C,
and VLDL-C. At all visits, LDL-C was calculated using the
Friedewald equation. At Visit 1 and Visit 1.1 direct LDL-C were
used if at the same visit TG >400 mg/dL (4.52 mmol/L). These
LDL-C values were used for the evaluation of the LDL-C inclusion
criterion (LDL-C qualifying measurements for randomization) and for
the assessment of changes in the statin therapy when LDL-C was not
at goal. At all remaining visits (except Visit 2 and Visit 4) LDL-C
was measured by direct LDL cholesterol or by preparative
ultracentrifugation if at the same visit TG >400 mg/dL (4.52
mmol/L). In addition, irrespective of the TG levels, at Visit 2 (0
Months of Follow-up, baseline) and at Visit 4 (12 Months of
Follow-up), LDL-C were measured by preparative ultracentrifugation.
These preparative ultracentrifugation LDL-C measurements were used
in the statistical analysis including the calculation of the
percent change from baseline (1 year versus baseline). Hopkins
LDL-C was calculated for each visit.
Genetic Testing:
A fasting blood sample was stored for future genetic testing at the
discretion of the Sponsor. The specifics of this test were
determined at a later date. This sample was optional as local
regulations may prohibit genetic samples to be collected or shipped
outside the country, or patients may not have consented. Research
on genetic testing looked for links between genes and certain
diseases, including their treatment(s) such as medicines and
medical care. The blood samples were collected in the study center
with the regular protocol-required labs. Each patient tube with a
sample for genetic testing were labeled with patient number only.
The site maintained a Subject Code Identification List for
cross-reference. The patient number did not contain any
identifiable information (i.e., patient initials, date of birth,
etc.). Un-analyzed samples were stored frozen by the Sponsor for a
period of up to 2 years following the end of the study, at which
time they were destroyed. If samples were tested, results were not
reported to the patient, parents, relatives, or attending physician
and were not recorded in the patient's medical records. There was
no follow-up contact with the sites or patients regarding this
sample. The subject could withdraw their consent for genetic
testing at any time up to analysis, even after the sample had been
obtained. The subject could notify the site in writing that they
withdraw their consent for the genetic testing portion of the
study, and it was documented by the site in the subject chart, as
well as captured in the CRF. The lab was notified to pull the
sample and destroy it. Potential genetic bioassays may have been
performed and may have been as broad as a genome-wide association
study (GWAS) or as limited as a single gene-target approach;
potential target genes include, but are not limited to the genes
encoding: Apo C3, Apo A5, CETP, LPL, PCSK9, TNF.alpha., TNF.beta.,
ALOX5, COX2, FABP genes, haptoglobin 1 and haptoglobin 2.
Biomarkers Assays:
The biomarker assays included: hsCRP, Apo B and hsTnT.
Additional Laboratory Tests:
Additional laboratory tests were performed and included: A urine
pregnancy test was administered to women of childbearing potential
at certain visits as listed in schedule of procedures (Table 1).
The urine pregnancy tests was performed at the Research Site
utilizing marketed test kits, or at a certified clinical
laboratory; A fasting blood sample (10 mL) for archiving. This
sample was collected only at sites in countries where allowed by
local regulations and at sites for which approved by the IRB or
IEC. The plasma from the archiving sample was stored frozen in 2
separate equal aliquots, and was used at the Sponsor's discretion
to perform repeat analyses described in the protocol or to perform
other tests related to cardiovascular health; and Potential
non-genetic bioassays were performed, including but not limited to:
Apo A1, Apo C3, Apo E, NMR lipid profile (particle size and
number), oxidized LDL, Lp(a), Lp-PLA2, serum fatty-acids
concentrations, and gamma-glutamyltransferase (GGT).
Blinding of Laboratory Results:
All efficacy laboratory results during the double-blind period of
the trial were blinded (values not provided) to patients,
investigators, pharmacists and other supporting staff at the
Research Sites, personnel and designees of the Sponsor, study
administrators and personnel at the organization(s) and vendors
managing and/or supporting the study, with the exception of the
laboratory personnel conducting the assays. To ensure patient
safety, hsTnT values were reported to the site.
Flagging of Critical Lab Values:
Critical lab values are values that may have warranted medical
intervention to avoid possible harm to a patient. Critical lab
values were defined in the Laboratory Manual for the study, and the
Research Site was notified of the occurrence of a critical lab
value (critical high or critical low) by a special annotation
(flag) in the laboratory reports provided to the Research Sites.
Although laboratory values that were part of the efficacy endpoints
during the double-blind period of the study were not provided to
the Research Site, the sites were notified when the TG value of a
patient sample was >1000 mg/dL (11.29 mmol/L) (critical high TG
value) or if the LDL-C values of a patient sample was >130 mg/dL
(3.37 mmol/L) (critical high LDL-C value). These critical high
values were confirmed by a repeat measurement (new fasting blood
sample) within 7 days. TG value of >2000 mg/dL (22.58 mmol/L)
were also flagged, so that appropriate medical action could be
taken by the investigator as soon as possible.
If TG values were confirmed critically high, patients could be
discontinued from study drug with the option to remain on study.
The investigator used the best clinical judgment for each patient
which included the use of approved TG-lowering medications after
patients had discontinued from study drug. If LDL-C values were
confirmed critically high, the investigator needed to take
appropriate medical action which included: reinforcing/intensifying
therapeutic lifestyle changes (including diet and physical
activity), increasing the dose of the present statin therapy,
adding ezetimibe, or prescribing a more potent statin to lower
LDL-C. The investigator used the best clinical judgment for each
patient.
Medical Procedures
Medical, Surgical and Family History:
Medical history, including family history and details regarding all
illnesses and allergies, date(s) of onset, status of current
condition, and smoking and alcohol use were collected on all
patients.
Demographics:
Demographic information including day, month, and year of birth,
race, and gender were collected for all patients.
Vital Signs and Patient Measurements:
Vital signs included systolic and diastolic blood pressure, heart
rate, respiratory rate, and body temperature. Blood pressure was
measured using a standardized process: Patient sat for .gtoreq.5
minutes with feet flat on the floor and measurement arm supported
so that the midpoint of the manometer cuff was at heart level; and
Used a mercury sphygmomanometer or automatic blood pressure device
with an appropriately sized cuff with the bladder centered over the
brachial artery.
Blood pressure was recorded to the nearest 2 mmHg mark on the
manometer or to the nearest whole number on an automatic device. A
blood pressure reading was repeated 1 to 2 minutes later, and the
second reading recorded to the nearest 2 mmHg mark.
The baseline value categories and post-baseline endpoint value
categories shown in Table 6 were measured and presented.
Definitions for potentially clinically significant (PCS) vital
signs treatment-emergent values are defined below in Table 7.
TABLE-US-00007 TABLE 6 Vital Signs Value Categories Vital Sign Low
Normal High Systolic Blood Pressure .ltoreq.90 mmHg >90 mmHg to
<160 mmHg .gtoreq.160 mmHg Diastolic Blood Pressure .ltoreq.50
mmHg >50 mmHg to <100 mmHg .gtoreq.100 mmHg Pulse .ltoreq.50
beats/min >50 beats/min to <90 beats/min .gtoreq.90
beats/min
TABLE-US-00008 TABLE 7 Potentially Clinically Significant Vial
Signs Value Definitions Vital Sign PCS Low PCS High Systolic Blood
.ltoreq.90 mmHg AND .gtoreq.160 mmHg AND Pressure decrease of
.gtoreq.20 mmHg; increase of .gtoreq.20 mmHg; .ltoreq.90 mmHg;
.gtoreq.160 mmHg; decrease of .gtoreq.20 mmHg increase of
.gtoreq.20 mmHg Diastolic Blood .ltoreq.50 mmHg AND .gtoreq.100
mmHg AND increase Pressure decrease of .gtoreq.10 mmHg; of >10
mmHg; .ltoreq.50 mmHg; .gtoreq.100 mmHg; decrease of >10 mmHg
increase of 10 mmHg Pulse .ltoreq.50 beats/min AND .gtoreq.90
beats/min AND decrease of .gtoreq.15 beats/min; increase of
.gtoreq.15 beats/min; .ltoreq.50 beats/min; .gtoreq.90 beats/min;
decrease of .gtoreq.15 beats/min increase of .gtoreq.15
beats/min
Number (%) of patients with any post-baseline PCS vital sign values
was summarized by treatment group. A listing of patients who meet
the threshold criteria was provided.
Physical Examination:
A physical examination included source documentation of general
appearance, skin, and specific head and neck, heart, lung, abdomen,
extremities, and neuromuscular assessments.
Height, Weight and Body Mass Index:
Height and weight were measured. Measurement of weight was
performed with the patient dressed in indoor clothing, with shoes
removed, and bladder empty.
Waist Circumference:
Waist circumference was measured with a tape measure, as follows:
Start at the top of the hip bone then bring the tape measure all
the way around--level with the navel. Make sure the tape measure is
snug, but without compressing the skin, and that it is parallel
with the floor. Patients should not have held their breath while
measuring waist circumference.
12-Lead Electrocardiogram (ECG):
ECGs (standard 12-lead) were obtained annually. Site personnel made
every attempt to perform a patient's ECG using the same equipment
at each visit. ECGs were reviewed by the site for the detection of
silent MI. Silent MIs were sent for event adjudication. All
post-randomization ECGs (protocol-specified and other) were sent to
the CEC for evaluation of silent MI. The 12-lead ECG parameters
included Heart Rate (bpm), PR Interval (msec), QRS Interval (msec),
QT Interval (msec), and QTc Interval (msec) were measured, and
Overall Interpretation and Silent MI (Yes/No) were summarized for
all patients at Screening (Visit 1), Randomization visit (Visit 2;
Day 0) and all other follow-up visits including the last visit of
the study.
A treatment-emergent PCS high value at any time was defined as a
change from a value less than or equal to the defined PCS value at
baseline to a PCS high value at any post-baseline measurement. A
treatment-emergent PCS low value at any time was defined as a
change from a value greater than or equal to the lower PCS value at
baseline to a PCS low value at any post-baseline measurement. Table
8 provides the PCS ECG values.
TABLE-US-00009 TABLE 8 Potentially Clinically Significant ECG Value
Definitions ECG Parameter PCS Low PCS High PR Interval <120 msec
>120 msec and increase of >20 msec from baseline QRS Interval
N/A >110 msec QTc N/A >500 msec
Number (%) of patients with post-baseline PCS ECG values were
presented by treatment group. A listing of subjects with
potentially clinically significant changes in ECG values was
included.
Treatment and Procedures
Treatment Regimen, Dosage, and Duration:
Eligible study patients were randomly assigned on Day 0 to one of
the 2 treatment groups. Patients in each group received either 4
g/day AMR101 or placebo for up to 6.5 years, depending on
individual date of randomization and overall study stop date
according to Table 9. The daily dose of study drug was 4 capsules
per day taken as two capsules taken on two occasions per day (2
capsules were given twice daily).
TABLE-US-00010 TABLE 9 Dosing Schedule during the Treatment Period
Treatment Group Daily Dose Number of Capsules per Day 1 4 g 4
capsules of 1000 mg AMR101 2 Placebo 4 capsules of matching
placebo
Patients were instructed to take study drug with food (i.e., with
or at the end of their morning and evening meals). On days that
patients were scheduled for study visits, the daily dose of study
drug was administered by site personnel with food provided by the
site following collection of all fasting blood samples. For the
purposes of this study, fasting was defined as nothing by mouth
except water (and any essential medications) for at least 10 hours.
Treatment Assignment
Identification Number:
A unique patient identification number (patient number) was
established for each patient at each site. The patient number was
used to identify the patient throughout the study and was entered
on all documentation. If a patient was not eligible to receive
treatment, or if a patient discontinued from the study, the patient
number could not be reassigned to another patient. The patient
number was used to assign patients to one of the 2 treatment groups
according to the randomization schedule.
Drug Randomization:
Only qualified patients who meet all of the inclusion criteria and
none of the exclusion criteria were randomized and received study
medication starting at Visit 2 (Day 0). Eligible patients were
randomly assigned to one of the 2 treatment groups. Randomization
was stratified by CV risk category, use of ezetimibe and by
geographical region (Westernized, Eastern European, and Asia
Pacific countries). Approximately 70% of randomized patients were
in the CV Risk Category 1, including patients with established CVD,
and approximately 30% of randomized patients were in the CV Risk
Category 2, including patients with diabetes and at least one
additional risk factor but no established CVD. Enrollment with
patients of a CV risk category was stopped when the planned number
of patients in that risk category was reached.
Emergency Unblinding:
In an emergency, when knowledge of the patient's treatment
assignment was essential for the clinical management or welfare of
the patient, the investigator could request the patient's treatment
assignment for unblinding. Prior to unblinding the patient's
individual treatment assignment, the investigator assessed the
relationship of an adverse event to the administration of the study
drug (Yes or No). If the blind was broken for any reason, the
investigator recorded the date and reason for breaking the blind on
the appropriate Case Report Form (CRF) and source documents.
Compliance Control:
Unless clear contraindications arise, patients were strongly
encouraged to adhere to their treatment regimen with the study drug
for the duration of the trial. Any interruptions of therapy were,
if possible, brief (e.g., <4 weeks) and only for clinically
indicated reasons, such as adverse events. Discontinuations were
discouraged as much as possible. Any discontinuations were based on
compelling clinical reasons. For every patient, an assessment of
compliance to the study drug treatment regimen was obtained at each
scheduled visit. Study medication was dispensed in amounts
exceeding the amount required for the study. Patients were
instructed to return all unused study medication at the next visit.
Compliance to the study drug regimen was evaluated at each visit by
counting unused capsules. Discrepancies were evaluated and
discussed with each patient to assess compliance. If compliance was
unsatisfactory, the patient was counseled about the importance of
compliance to the dosing regimen. At the end of the study, the
final study medication compliance was determined by unused capsule
count.
Study Restrictions
Concomitant Medications During Treatment/Follow-Up Period:
Any medications administered during the study period were
documented on the Concomitant Medication CRF. Patients had not
taken any investigational agent within 90 days prior to screening.
Patients could not participate in any other investigational
medication trial while participating in this study. The following
non-study drug related, non-statin, lipid-altering medications and
supplements, and foods were prohibited during the study (from Visit
1 until after the Last Visit-End of Study), except for compelling
medical reasons in ODIS patients: niacin >200 mg/day; fibrates;
prescription omega-3 fatty acid medications; dietary supplements
containing omega-3 fatty acids (e.g., flaxseed, fish, krill, or
algal oils); bile acid sequestrants; PCSK9 inhibitors;
cyclophosphamide; and systemic retinoids.
If any of these products were used during the treatment/follow-up
period of the study, it was for compelling medical reasons in ODIS
patients, and documented in the Concomitant Medication CRF. If the
ODIS patient agreed to restart study medication, the use of
excluded medication was discontinued. Foods enriched with omega-3
fatty acids were strongly discouraged after Visit 1 for the
duration of the study (does not apply to The Netherlands or Canada
only. Therefore, all centers in The Netherlands and Canada ignored
this request). The following products were allowed: statins,
ezetimibe, and herbal products & dietary supplements not
containing omega-3 fatty acids.
Statins: The same statin at the same dose was continued until the
end of the study, unless deemed medically necessary to change
because of an adverse event or lack of efficacy (LOE). It was
preferred that if LOE was the determining factor that ezetimibe was
added to the present dose; Switching between a brand name statin
and the generic version of the same statin was allowed at any time
during the study; Statins were administered with or without
ezetimibe; Based on the FDA recommendation, simvastatin 80 mg was
used only in patients who had been taking this dose for 12 months
or more and had not experienced any muscle toxicity. (See
reference: FDA Drug Safety Communication: Ongoing safety review of
high-dose Zocor (simvastatin) and increased risk of muscle injury.
(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetynformationforPat-
ie ntsandProviders/ucm204882.htm); and Changing of the type of
statin or the statin dose during the treatment/follow-up period of
the study was only done for compelling medical reasons and was
documented in the CRF. Maintaining statin therapy throughout the
study was important and, in the rare circumstance that it became
medically compelling to discontinue statin use, the patient could
remain in the study and on study medication with approval from the
Medical Monitor. Under such conditions, resumption of statin
therapy was attempted when/if medically appropriate. If the level
of LDL-C exceeded 130 mg/dL (3.37 mmol/L) during the study (initial
measurement and confirmed by a second determination at least 1 week
later), the investigator either increased the dose of the present
statin therapy or added ezetimibe to lower LDL-C. The investigator
used the best clinical judgment for each patient.
Ldl-C Rescue:
If the level of LDL-C exceeded 130 mg/dL (3.37 mmol/L) during the
study (initial measurement and confirmed by a second determination
at least 1 week later), the investigator either increased the dose
of the present statin therapy or added ezetimibe to lower LDL-C.
The investigator used the best clinical judgment for each
patient.
No data were available with regard to potential interactions
between ethyl-EPA and oral contraceptives. There were no reports
suggesting that omega-3 fatty acids, including ethyl-EPA, would
decrease the efficacy of oral contraceptives.
Medications that were excluded if not at a stable dose for
.gtoreq.28 days prior to screening, could be initiated
post-randomization if medically warranted (i.e., tamoxifen,
estrogens, progestins, thyroid hormone therapy, systemic
corticosteroids and HIV-protease inhibitors).
Patient Restrictions:
Beginning at the screening visit, all patients were instructed to
refrain from excessive alcohol consumption, to follow a physician
recommended diet and to maintain it through the duration of the
study. Excessive alcohol consumption is on average 2 units of
alcohol per day or drinking 5 units or more for men or 4 units or
more for women in any one hour (episodic excessive drinking or
binge drinking). A unit of alcohol is defined as a 12-ounce (350
mL) beer, 5-ounce (150 mL) wine, or 1.5-ounce (45 mL) of 80-proof
alcohol for drinks.
Investigational Product
Clinical Trial Material:
The following clinical materials were supplied by the Sponsor:
AMR101 1000 mg capsules Placebo capsules (to match AMR 101 1 g
Capsules)
The Sponsor supplied sufficient quantities of AMR101 1000 mg
capsules and placebo capsules to allow for completion of the study.
The lot numbers of the drugs supplied were recorded in the final
study report. Records were maintained indicating the receipt and
dispensation of all drug supplies. At the conclusion of the study,
any unused study drug was destroyed.
Pharmaceutical Formulations:
AMRI01 1000 mg and placebo capsules (paraffin) were provided in
liquid-filled, oblong, gelatin capsules. Each capsule was filled
with a clear liquid (colorless to pale yellow in color). The
capsules were approximately 25.5 mm in length with a diameter of
approximately 9.5 mm.
Labeling and Packaging:
Study medication was packaged in high-density polyethylene bottles.
Labeling and packaging was performed according to GMP guidelines
and all applicable country-specific requirements. The bottles were
numbered for each patient based on the randomization schedule. The
patient randomization number assigned by IWR or a designee of the
Sponsor for the study (if no IWR system was used), corresponds to
the number on the bottles. The bottle number for each patient was
recorded in the Electronic Data Capture (EDC) system for the
study.
Dispensing Procedures and Storage Conditions
Dispensing Procedures:
At Visit 2 (Day 0), patients were assigned a study drug according
to their treatment group determined by the randomization schedule.
Once assigned to a treatment group, patients received study drug
supplies. At each visit, patients brought unused drug supplies
dispensed to them earlier. From the drug supplies assigned to each
patient, site personnel administered the drug while the patients
were at the Research Site. The investigator or designee contacted
the IWR system or a designee of the Sponsor for the study (if no
IWR system is used) when any unscheduled replacements of study
medication were needed. During the last visit of the treatment
period, patients brought the unused drug supplies for site
personnel to calculate the final study medication compliance by
unused capsule count.
Storage Conditions:
At the Research Sites, study drugs were stored at room temperature,
68.degree. F. to 77.degree. F. (20.degree. C. to 25.degree. C.).
Storage temperature did not go below 59.degree. F. (15.degree. C.)
or above 86.degree. F. (30.degree. C.) and the drug was stored in
the original package. Study drugs were stored in a pharmacy or
locked and secure storage facility, accessible only to those
individuals authorized by the investigator to dispense the drug.
The investigator or designee kept accurate dispensing records. At
the conclusion of the study, study site personnel accounted for all
used and unused study drug. Any unused study drug was destroyed.
The investigator agreed not to distribute study drug to any
patient, except those patients participating in the study.
Efficacy Assessments
Specification of Variables and Procedures:
The primary endpoint and the majority of the secondary and tertiary
endpoints were based on clinical events related to CVD and
mortality. All events occurring between randomization and the study
end date (inclusive) were recorded. Only adjudicated events were
included in the final analyses.
Primary Efficacy Endpoint:
The primary efficacy endpoint was time from randomization to the
first occurrence of the composite of the following clinical events:
CV death; nonfatal MI (including silent MI; ECGs were performed
annually for the detection of silent MIs); nonfatal stroke;
coronary revascularization; and unstable angina determined to be
caused by myocardial ischemia by invasive/non-invasive testing and
requiring emergent hospitalization. The first occurrence of any of
these major adverse vascular events during the follow-up period of
the study were included in the incidence.
Secondary Efficacy Endpoints:
The key secondary efficacy endpoint was the time from randomization
to the first occurrence of the composite of CV death, nonfatal MI
(including silent MI), or nonfatal stroke. Other secondary efficacy
endpoints were time from randomization to the first occurrence of
the individual or composite endpoints as follows (tested in the
order listed): The composite of CV death or nonfatal MI (including
silent MI); Fatal or nonfatal MI (including silent MI);
Non-elective coronary revascularization represented as the
composite of emergent or urgent classifications; CV death; Unstable
angina determined to be caused by myocardial ischemia by
invasive/non-invasive testing and requiring emergent
hospitalization; Fatal and nonfatal stroke; The composite of total
mortality, nonfatal MI (including silent MI), or nonfatal stroke;
and/or Total mortality.
For the secondary endpoints that count a single event, the time
from randomization to the first occurrence of this type of event
was counted for each patient. For secondary efficacy endpoints that
were composites of two or more types of events, the time from
randomization to the first occurrence of any of the event types
included in the composite were counted for each patient.
Tertiary Efficacy Endpoints:
The following tertiary endpoints were evaluated as supporting
efficacy and safety analyses. Where applicable and unless specified
otherwise, endpoint analyses were conducted as time from
randomization to the first occurrence of the individual or
composite endpoint as follows: Total CV events analysis defined as
the time from randomization to occurrence of the first and all
recurrent major CV events defined as CV death, nonfatal MI
(including silent MI), nonfatal stroke, coronary revascularization,
or unstable angina determined to be caused by myocardial ischemia
by invasiveinon-invasive testing and requiring emergent
hospitalization; Primary composite endpoint in subset of patients
with diabetes mellitus at baseline; Primary composite endpoint in
the subset of patients with metabolic syndrome at baseline with
waist circumference cut points specifically set at .gtoreq.35
inches (88 cm) for all women and Asian, Hispanic, or Latino men,
and 40 inches (102 cm) for all other men; Primary composite
endpoint in the subset of patients with impaired glucose metabolism
at baseline (Visit 2 FBG of 100-125 mg/dL); Key secondary composite
endpoint in the subset of patients with impaired glucose metabolism
at baseline (Visit 2 FBG 100-125 mg/dL); The composite of CV death,
nonfatal MI (including silent MI), nonfatal stroke, cardiac
arrhythmia requiring hospitalization of .gtoreq.24 hours, or
cardiac arrest; The composite of CV death, nonfatal MI (including
silent MI), non-elective coronary revascularizations (defined as
emergent or urgent classifications), or unstable angina determined
caused by myocardial ischemia by invasive/non-invasive testing and
requiring emergent hospitalization; The composite of CV death,
nonfatal MI (including silent MI), non-elective coronary
revascularizations (defined as emergent or urgent classifications),
unstable angina determined caused by myocardial ischemia by
invasive/non-invasive testing and requiring emergent
hospitalization, nonfatal stroke, or PVD requiring intervention,
such as angioplasty, bypass surgery, or aneurism repair; The
composite of CV death, nonfatal MI (including silent MI),
non-elective coronary revascularizations (defined as emergent or
urgent classifications), unstable angina determined caused by
myocardial ischemia by invasive/non-invasive testing and requiring
emergent hospitalization, PVD requiring intervention, or cardiac
arrhythmia requiring hospitalization of 24 hours; New CHF; New CHF
as the primary cause of hospitalization; Transient ischemic attack
(TIA); Amputation for PVD; Carotid revascularization; All coronary
revascularizations defined as the composite of emergent, urgent,
elective, or salvage; Emergent coronary revascularizations; Urgent
coronary revascularizations; Elective coronary revascularizations;
Salvage coronary revascularizations; Cardiac arrhythmias requiring
hospitalization of 24 hours; Cardiac arrest; Ischemic stroke;
Hemorrhagic stroke; Fatal or nonfatal stroke in the subset of
patients with a history of stroke prior to baseline; New onset
diabetes, defined as Type 2 diabetes newly diagnosed during the
treatment/follow-up period; New onset hypertension, defined as
blood pressure .gtoreq.140 mmHg systolic OR .gtoreq.90 mm Hg
diastolic newly diagnosed during the treatment/follow-up period;
Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hsCRP
(hsCRP and log[hsCRP]), hsTnT, and RLP-C (to be estimated from
standard lipid panel, RLP-C=TC-HDL-C-LDL-C [Varbo 2014]), (based on
ITT estimands): Assessment of the relationship between baseline
biomarker values and treatment effects within the primary and key
secondary composite endpoints; Assessment of the effect of AMR101
on each marker; and Assessment of the relationship between
post-baseline biomarker values and treatment effects within the
primary and key secondary composite endpoints by including
post-baseline biomarker values (for example, at 4 months, or at 1
year) as a covariate. Change in body weight; and Change in waist
circumference.
Where applicable and unless specified otherwise, for the tertiary
endpoints that count a single event, the time from randomization to
the first occurrence of this type of event was counted in each
patient. Similarly, where applicable and unless specified
otherwise, for tertiary endpoints that were composites of two or
more types of events, the time from randomization to the first
occurrence of any of the event types included in the composite was
counted in each patient.
Other sensitivity, supportive, and exploratory analyses for the
primary efficacy endpoint were carried out, namely, an on-treatment
analysis which included primary event onset up to 0 and 30-days
after the permanent discontinuation of the drug.
The following clinical events that were positively adjudicated by
the Clinical Endpoint Committee were analyzed as tertiary endpoints
for the ITT intent-to-treat (ITT) population: Composition of total
mortality, or congestive heart failure (CHF); Composite of CV
death, or new CHF; Sudden cardiac death; Peripheral artery disease
(PAD); and Atrial fibrillation, or atrial flutter.
The above tertiary endpoints were analyzed similarly as the primary
endpoint.
In addition, the following were analyzed as tertiary endpoints for
the ITT population: Relationship between on-treatment
high-sensitivity C-reactive protein (hsCRP) and the primary key
secondary endpoints; and Relationship between on-treatment serum
eicosapentaenoic acid (EPA) and the primary and key secondary
endpoints.
To assess the relationship between on-treatment hsCRP and the
primary and key secondary endpoints, subgroup analyses were carried
out as done for the ITT population for patients grouped according
to values greater or equal to or less than 2 mg/dL at baseline and
at 2 years. To assess the relationship between on-treatment serum
EPA and the primary and key secondary endpoints, Kaplan-Meier (KM)
curves were produced for AMRI01 treated patients grouped into
tertiles based on their values at year 1 and were compared with the
placebo-treated patients.
Safety Assessments
Specification of Variables and Procedures:
Safety assessments included adverse events, clinical laboratory
measurements (chemistry, hematology), 12-lead ECGs, vital signs
(systolic and diastolic blood pressure, heart rate, respiratory
rate, and body temperature), weight, waist circumference, and
physical examinations as per Study Procedures in Table 1. A
complete medical, surgical and family history was completed at
Visit 1. All laboratory test results were evaluated by the
investigator as to their clinical significance. Any observations at
physical examinations or laboratory values considered by the
investigator to be clinically significant were considered an
adverse event.
Adverse Events:
An adverse event is defined as any untoward medical occurrence,
which does not necessarily have a causal relationship with the
medication under investigation. An adverse event can therefore be
any unfavorable and/or unintended sign (including an abnormal
laboratory finding), symptom, or disease temporally associated with
the use of an investigational medication product, whether or not
related to the investigational medication product. All adverse
events, including observed or volunteered problems, complaints, or
symptoms, were recorded on the appropriate CRF. Each adverse event
was evaluated for duration, intensity, and causal relationship with
the study medication or other factors.
Adverse events, which included clinical laboratory test variables,
were monitored from the time of informed consent until study
participation was complete. Patients were instructed to report any
adverse event that they experienced to the investigator. Beginning
with Visit 2, investigators assessed for adverse events at each
visit and recorded the event on the appropriate adverse event
CRF.
Wherever possible, a specific disease or syndrome rather than
individual associated signs and symptoms was identified by the
investigator and recorded on the CRF. However, if an observed or
reported sign or symptom was not considered a component of a
specific disease or syndrome by the investigator, it was recorded
as a separate adverse event on the CRF.
Any medical condition that was present when a patient was screened
or present at baseline that did not deteriorate were reported as an
adverse event. However, medical conditions or signs or symptoms
present at baseline and that changed in severity or seriousness at
any time during the study were reported as an adverse event.
Clinically significant abnormal laboratory findings or other
abnormal assessments that were detected during the study or were
present at baseline and significantly worsened were reported as
adverse events or SAEs. The investigator exercised his or her
medical and scientific judgment in deciding whether an abnormal
laboratory finding, or other abnormal assessment was clinically
significant.
The investigator rated the severity (intensity) of each adverse
event as mild, moderate, or severe, and also categorized each
adverse event as to its potential relationship to study drug using
the categories of Yes or No. The severity was defined as: Mild--An
event that is usually transient in nature and generally not
interfering with normal activities. Moderate--An event that is
sufficiently discomforting to interfere with normal activities.
Severe--An event that is incapacitating with inability to work or
do usual activity or inability to work or perform normal daily
activity.
Causality Assessment:
The relationship of an adverse event to the administration of the
study drug was assessed according to the following definitions: No
(unrelated, not related, no relation)--The time course between the
administration of study drug and the occurrence or worsening of the
adverse event rules out a causal relationship and another cause
(concomitant drugs, therapies, complications, etc.) is suspected.
Yes (related, probably related, possibly related)--The time course
between the administration of study drug and the occurrence or
worsening of the adverse event is consistent with a causal
relationship and no other cause (concomitant drugs, therapies,
complications, etc.) can be identified.
The following factors were also considered: The temporal sequence
from study medication administration; The event occurred after the
study medication was given. The length of time from study
medication exposure to event was evaluated in the clinical context
of the event; Underlying, concomitant, intercurrent diseases; Each
report was evaluated in the context of the natural history and
course of the disease being treated and any other disease the
patient may have had; Concomitant medication; The other medications
the patient was taking or the treatment the patient received were
examined to determine whether any of them might have caused the
event in question; Known response pattern for this class of study
medication; Clinical and/or preclinical data may have indicated
whether a particular response was likely to be a class effect;
Exposure to physical and/or mental stresses; The exposure to stress
might induce adverse changes in the patient and provide a logical
and better explanation for the event; The pharmacology and
pharmacokinetics of the study medication; and The known
pharmacologic properties (absorption, distribution, metabolism, and
excretion) of the study medication were considered.
Unexpected Adverse Events:
An unexpected adverse event is an adverse event either not
previously reported or where the nature, seriousness, severity, or
outcome is not consistent with the current Investigator's
Brochure.
Serious Adverse Events:
A serious adverse event (SAE) is defined as an adverse event that
meets any of the following criteria: Results in death; Is
life-threatening--The term "life-threatening" in the definition of
"serious" refers to an event in which the patient was at risk of
death at the time of the event. It does not refer to an event,
which hypothetically might have caused death, if it were more
severe; Requires hospitalization or prolongation of existing
hospitalization. In general, hospitalization for treatment of a
pre-existing condition(s) that did not worsen from baseline was not
considered adverse events and was not reported as SAEs; Results in
disability/incapacity; Is a congenital anomaly/birth defect; and Is
an important medical event. Important medical events that may not
result in death, be life threatening, or require hospitalization
were considered an SAE when, based upon appropriate medical
judgment, they may have jeopardized the patient and may have
required medical or surgical intervention to prevent one of the
outcomes listed above. Examples of such medical events included
allergic bronchospasm requiring intensive treatment in an emergency
room or at home, blood dyscrasias or convulsions that did not
result in inpatient hospitalizations, or the development of drug
dependency.
By design of this study SAEs that were endpoint events were only
recorded for the endpoint determination and not captured as SAEs.
The intention was that the endpoint events were reported to IRBs as
SAEs, unless the IRB required that these were reported.
Investigators specifically informed their institution/IRB of this
plan and confirm whether or not they wanted the endpoint events
reported. By agreement with the US FDA, these endpoints were also
not reported to the US FDA as SAEs; rather they were reported as
endpoint events. Following adjudication if the event was determined
to not meet the criteria for an event, the event was evaluated as
an SAE beginning with that day as Day 0.
Adverse Events of Special Interest:
Bleeding-related adverse events, glucose control (fasting blood
glucose and HbA1c), and indicators of hepatic disorders (e.g., ALT
or AST increases >3.times.ULN, total bilirubin increases of
2.times.ULN) were summarized separately and compared between
treatment groups.
Serious Adverse Event Reporting--Procedure for Investigators
Initial Reports:
All SAEs occurring from the time of informed consent until 28 days
following the last administration of study medication were reported
to the Sponsor or designee within 24 hours of the knowledge of the
occurrence (this refers to any adverse event that meets any of the
aforementioned serious criteria). SAEs that the investigator
considered related to study medication occurring after the 28-day
follow-up period were also reported to the Sponsor or designee. The
investigator was required to submit SAE reports to the
Institutional Review Board (IRB) or Independent Ethics Committee
(IEC) in accordance with local requirements. All investigators
involved in studies using the same investigational medicinal
product (IMP) received any Suspected Unexpected Serious Adverse
Reaction (SUSAR) reports for onward submission to their local IRB
as required. All reports sent to investigators were blinded. In
addition, regulatory agencies were notified of SAEs per the
requirements of the specific regulatory jurisdiction regulations
and laws.
Follow-Up Reports:
The investigator followed the patient until the SAE subsided, or
until the condition became chronic in nature, stabilized (in the
case of persistent impairment), or the patient died. Within 24
hours of receipt of follow-up information, the investigator updated
the SAE form electronically in the EDC system for the study and
submitted any supporting documentation (e.g., laboratory test
reports, patient discharge summary, or autopsy reports) to the
Sponsor or designee via fax or email.
Reporting by the Sponsor:
IRBs and IECs were informed of SUSARs according to local
requirements. Cases were unblinded for reporting purposes as
required.
Exposure in Utero During Clinical Trials:
If a patient became pregnant during the study, the investigator
reported the pregnancy to the Sponsor or designee within 24 hours
of being notified. The Sponsor or designee then forwarded the
Exposure in Utero form to the investigator for completion. The
patient was followed by the investigator until completion of the
pregnancy. If the pregnancy ended for any reason before the
anticipated date, the investigator notified the Sponsor or
designee. At the completion of the pregnancy, the investigator
documented the outcome of the pregnancy. If the outcome of the
pregnancy met the criteria for immediate classification as an SAE
(i.e., postpartum complication, spontaneous abortion, stillbirth,
neonatal death, or congenital anomaly), the investigator followed
the procedures for reporting an SAE.
Treatment Discontinuation/Patient Withdrawal
Patients could withdraw from the study at any time and for any
reason.
Study drug administration could also be discontinued at any time,
at the discretion of the investigator. In any case, follow-up for
efficacy and safety was continued in subjects that discontinued
therapy, but remained in the study (i.e., ODIS patients).
Reasons for Early Study Drug Discontinuation:
Study drug discontinuation was avoided as much as possible, but
could have been done for any of the following reasons: Patient
withdrew consent or requested early discontinuation from the study
for any reason. Patients were encouraged to continue to participate
in the study for the entire duration of the study even if they
choose not to take study medication any longer; Occurrence of a
clinical or laboratory adverse event, either serious or
non-serious, at the discretion of the investigator. The Sponsor or
designee was notified if a patient was discontinued because of an
adverse event or laboratory abnormality. It was recommended that,
unless clear contraindications arise, patients were strongly
encouraged to adhere to their treatment regimen with the study drug
for the duration of the trial. Any interruptions of therapy were,
if possible, brief (e.g., <4 weeks) and only for clinically
indicated reasons, such as adverse events. The following were
considered a reason for discontinuation: ALT >3.times.ULN and
bilirubin >1.5.times.ULN; ALT >5.times.ULN; ALT
>3.times.ULN and appearance or worsening of hepatitis; ALT
>3.times.ULN persisting for >4 weeks; and/or ALT
>3.times.ULN and cannot be monitored weekly for 4 weeks Any
medical condition or personal circumstance that, in the opinion of
the investigator, exposed the patient to risk by continuing in the
study or precluded adherence to the protocol; Sponsor discontinued
the study; Investigative site closure, in the event that: Another
investigative site cannot accommodate the patient, or The patient
was unable or unwilling to travel to another investigative site;
and/or A TG value was flagged as critically high, i.e., >1000
mg/dL (11.29 mmol/L), and confirmed as critically high by a repeat
measurement (new fasting blood sample) within 7 days. In this case,
a patient could be discontinued from study drug (with the option to
remain ODIS) and other lipid-altering medications may be
(re)initiated. If the TG value was flagged as >2000 mg/dL (22.58
mmol/L) then appropriate medical action was taken by the
investigator as soon as possible.
Occurrence of an outcome event according to the judgment of the
investigator was not considered a valid reason for study drug
discontinuation. Patients whose treatment with study medication was
discontinued early, and had not withdrawn consent, stayed in the
study and were monitored until the end of the study. Patients that
continued in the study after .gtoreq.30 days cessation of therapy
were characterized as Off Drug In Study (ODIS). ODIS patients were
asked to return to the study site for an interim visit once the
patient had been off study drug for >30 days. Procedures at this
visit were consistent with those at Visit 5. If not
contraindicated, patients also had the option to restart study
medication at any point once characterized as ODIS. For patients
who discontinued study medication (e.g., for an AE that may or may
not have been drug-related), a brief therapy interruption could
have been followed with a re-challenge (re-initiating study
medication) as soon as clinically appropriate; thereby allowing a
causative role for study medication to be confirmed or ruled out
and continuing a patient in the study and on study drug if
appropriate. The reason for study drug discontinuation or
interruption was recorded on the CRF.
Follow-Up after Early Study Drug Discontinuation/Lost to
Follow-Up
Patients who prematurely discontinued study drug were not replaced.
All randomized patients were followed up until the study end date
or death, regardless of whether they discontinued study drug
prematurely or not. Any event occurring after early study drug
discontinuation was recorded up through the study end date. In
order to follow the medical status of the patients, especially when
they discontinued the study, investigators were encouraged to
obtain information from the patient's primary care practitioner
(physician or any other medical care provider). Investigators were
also requested to try as much as possible to re-contact those
patients at the end of the trial to obtain at least their vital
status as well as their status with respect to the primary
endpoint, and thus avoided lost to follow-up for the efficacy
assessment. If patients were lost to follow-up, the CRF was
completed up to the last visit or contact.
Statistics
Randomized Population:
The randomized population included all patients who sign the
informed consent form and are assigned a randomization number at
Visit 2 (Day 0).
Intent-to-Treat Population:
The ITT population included all patients who were randomized via
the IRWS (Interactive Web Response System). All efficacy analyses
were performed on the ITT population. Patients were analyzed
according to the randomized treatment.
Modified Intent-to-Treat Population:
The Modified Intent-to-Treat (mITT) population included all
randomized patients who had the study drug dispensed after
randomization. Groups were defined based on the randomized
treatment.
Per-Protocol Population:
The per-protocol (PP) population included all mITT patients without
any major protocol deviations, and who had .gtoreq.80% compliance
while on treatment. To be included in the PP population the minimum
time on therapy was 90 days.
Safety Population:
All safety analyses were conducted based on the safety population,
which is defined as all randomized patients. This was the same as
the ITT population.
Statistical Methods:
Safety and efficacy variables were analyzed using appropriate
statistical methods that were described in detail in a separate
Statistical Analysis Plan (SAP). The SAP was finalized before study
unblinding.
Patient Disposition and Demographic/Baseline Characteristics:
The number and percentage of patients was tabulated for each of the
following categories for each treatment group: Screened (total
only); Re-screened and reasons for re-screening (total only); ITT
overall and by stratification factors (CV risk, ezetimibe use, and
geographical region); mITT population; overall and by
stratification factors (CV risk, ezetimibe use, and geographical
region); PP population; overall and by stratification factors (CV
risk, ezetimibe use, and geographical region); Safety population;
Patients who completed the study; Patients who terminated from the
trial early and the primary reason for early termination; Patients
who terminated the trial early prior to having a confirmed primary
endpoint event; Patients with complete follow-up, defined as those
for whom all components of the primary endpoint have been
ascertained during the entire observation period (or until death);
and Patients who, at the time of study completion, were
discontinued from study drug prematurely, but continued within the
study (i.e. ODIS patients), along with the primary reason.
For randomized patients who discontinued treatment with study drug,
the primary reason for discontinuation was listed and summarized by
treatment group. Demographic and baseline characteristics,
including age, gender, ethnicity, race, height, body weight, BMI,
diabetes, hypertension, metabolic syndrome, overweight/obese/normal
according to BMI, and diabetes plus obesity were summarized using
descriptive statistics by treatment group in the ITT
population.
Demographic data and baseline characteristics were compared among
treatment groups for the ITT and PP population. Differences in
demographic and baseline characteristics were tested using a
chi-square test (for categorical variables) or t-test (for
continuous variables). The p-values used were considered
descriptive, primarily as an assessment of the balance between the
two groups. Age in years was calculated using the date of
randomization (Visit 2) and the date of birth.
Study Medication Exposure and Compliance:
Study drug exposure was summarized by treatment group using
descriptive statistics for each time point and overall. Overall
study drug compliance was calculated as the number of doses assumed
to be taken relative to scheduled dosing period as follows:
.times..times..times..times..times..times..times..times..times..times..ti-
mes..times..times..times..times..times..times..times..times..times..times.-
.times..times..times..times..times..times..times..times..times..times..tim-
es..times..times. ##EQU00001##
Overall percent compliance was calculated per patient in the ITT
and Modified ITT populations and summarized by treatment group
using descriptive statistics.
Concomitant Therapies:
Concomitant medication/therapy verbatim terms were coded using the
latest available version, prior to data base lock, of the World
Health Organization Drug Dictionary and the Anatomical Therapeutic
Chemical classification system. The numbers and percentages of
patients in each treatment group taking concomitant medications
were summarized. All verbatim descriptions and coded terms were
listed for all non-study medications.
Analysis of Efficacy:
For efficacy endpoints including CV events, only adjudicated events
were included in the final statistical analyses.
Summary Statistics:
Summary statistics (n, mean, standard deviation, median, minimum,
and maximum) for the baseline and post-baseline measurements, the
percent changes, or changes from baseline were presented by
treatment group and by visit for all efficacy variables analyzed.
The summary statistics included changes in body weight and body
mass index from baseline by treatment group and by visit.
Primary Endpoint Analyses:
The analysis of the primary efficacy endpoint was performed using
the log-rank test comparing the 2 treatment groups (AMR101 and
placebo) and including the stratification factor "CV risk
category", use of ezetimibe and geographical region (Westernized,
Eastern European, and Asia Pacific countries) (each as recorded in
the IWR at the time of enrollment) as covariates. The two-sided
alpha level for the primary analysis was reduced from 0.05 to
account for the interim analyses based on a group sequential design
with O'Brien-Fleming boundaries generated using the Lan-DeMets
alpha-spending function. The hazard ratio (HR) for treatment group
(AMRI 01 vs. placebo) from a Cox proportional hazard model that
included the stratification factor was also reported, along with
the associated 95% confidence interval (CI). Kaplan-Meier estimates
from randomization to the time to the primary efficacy endpoint
were plotted.
The size and direction of the treatment effects of the individual
components of the composite endpoint and their relative
contribution to the composite endpoint were determined as well. All
observed data that were positively adjudicated by the CEC,
including data after discontinuation of study treatment for
patients who discontinued study drug prematurely, were included in
the primary analysis. Patients who did not experience a primary
efficacy event prior to the end of the study or who withdraw from
the study early without a preceding primary efficacy event were
censored at the date of their last visit/phone contact. The longest
prespecified interval between visits (onsite or phone) was 90 days.
In view of the up to 90-day monitoring period for CV events, the
primary endpoint for patients who had a non-CV death within 90 days
of last contact without having had an earlier CV event was censored
at the time of death. The primary endpoint for patients who had a
non-CV death more than 90 days after last contact without having
had an earlier CV event were censored at the time of last
contact.
The primary analysis assumed that all silent MIs occurred on the
date of the first tracing indicative of a silent MI; a second
(sensitivity) analysis assumed that all silent MIs occurred on the
day after the last prior normal ECG; and a third (sensitivity)
analysis assumed that all silent MIs occurred at the mid-point
between the last normal ECG and the ECG with the new MI. All deaths
causally adjudicated as "undetermined" were combined with those
adjudicated as "CV deaths" for the primary analysis. A sensitivity
analysis of the CV death category was performed that excluded the
"undetermined cause of death" cohort.
The primary efficacy analysis was performed on the ITT population.
A sensitivity analysis was performed using the mITT and PP
populations. As a sensitivity analysis, patients who discontinued
study drug prematurely were censored for the primary composite
endpoint analysis on the date of drug discontinuation. The primary
analysis was repeated using this censoring rule for the mITT
population. As a supportive analysis, a multivariable, stratified
Cox proportional hazards model was constructed for the primary
endpoint to evaluate the treatment effect adjusting for important
covariates.
Secondary Endpoint Analyses:
The key secondary hypothesis was tested as part of the confirmatory
process only if the primary analysis was statistically significant.
For the analysis of secondary efficacy endpoints, the Type 1 error
was controlled by testing each endpoint sequentially, starting with
the key endpoint. Testing was done at a significance level
consistent with that used for the primary endpoint and ceased when
a secondary endpoint was found for which treatments did not
significantly differ. P-values were presented for all analyses, but
they were considered descriptive after the first non-significant
result was obtained. Each of the secondary endpoints were analyzed
by the same methods described for the primary efficacy endpoint.
Kaplan-Meier estimated, the log-rank test stratified by
stratification factors used at randomization, and the Cox
proportional hazards model including the stratification factors as
specified above for the primary efficacy endpoint, were summarized
by treatment group. In view of the 90-day monitoring period for CV
events, the key secondary endpoint for patients who had a non-CV
death within 90 days of last contact without having had an earlier
CV event was censored at the time of death. The key secondary
endpoint for patients who had a non-CV death more than 90 days
after last contact without having had an earlier CV event was
censored at the time of last contact. Kaplan-Meier curves
stratified by each stratification factor were presented. These
analyses were conducted for the ITT population.
Tertiary Endpoints Analyses:
Time-to-event tertiary endpoints were analyzed by the same methods
as described for the primary efficacy endpoint. Kaplan-Meier
estimates, the log-rank test stratified by stratification factors
used at randomization, and the Cox proportional hazards model as
specified for the primary efficacy endpoint, were summarized by
treatment group. In view of the 90-day monitoring period for CV
events, if applicable, tertiary endpoints for patients who had a
non-CV death within 90 days of last contact without having had an
earlier CV event were censored at the time of death. If applicable,
tertiary endpoints for patients who gad a non-CV death more than 90
days after last contact without having had an earlier CV event were
censored at the time of last contact. Kaplan-Meier curves
stratified by each of the stratification factors were
presented.
The fasting lipid panel was tested at Screening (Visit 1 or Visit
1.1), Randomization visit (Visit 2; Day 0), Visit 3 (Day 120;
.about.4 Months) and all other follow-up visits including the last
visit. For change from baseline to 1 year preparative
ultracentrifugation measurements for LDL-C were analyzed, unless
this value was missing. If the LDL-C preparative
ultracentrifugation values were missing, then another LDL-C value
was used, with prioritization of values obtained from LDL-C Direct
measurements, followed by LDL-C derived by the Friedewald
calculation (only for subjects with TG <400 mg/dL), and finally
LDL-C derived using the calculation published by Hopkins University
investigators (Martin S S, Blaha M J, Elshazly M B, et al.
Comparison of a novel method vs the Friedewald equation for
estimating low-density lipoprotein cholesterol levels from the
standard lipid profile. JAMA. 2013; 310:2061-8.). In addition,
change from baseline to day 120 in LDL-C utilizing Friedewald's and
Hopkins methods was analyzed, using the arithmetic mean of LDL-C
obtained at Visit 2 (Day 0) and the preceding Visit 1 (or Visit
1.1). If one of these values was missing, the single available
LDL-C value was used. LDL-C according to Hopkins was calculated at
each visit.
The randomization visit was considered Baseline. If a baseline
value was not available from the randomization visit, then the
latest screening value was used. For measurements of lipids,
lipoproteins and inflammatory markers, the change and the percent
change were summarized at each visit. Since these biomarkers are
typically not normally distributed, the Wilcoxon rank-sum test was
used for treatment comparisons of the percent change from baseline,
and medians and quartiles were provided for each treatment group.
The medians of the differences between the treatment groups and 95%
Cis were estimated with the Hodges-Lehmann method. In addition,
shift-tables were generated as appropriate.
As an additional exploratory analysis, the relationship between
post-baseline biomarker values and treatment effects with the
primary and key secondary endpoints were assessed by adding
biomarker values (for example, at 4 months, or at 1 year, etc.) as
time-dependent covariates in the Cox proportional hazards model.
Diagnostic plots for the proportional hazards assumption were
evaluated. Weight was measured at the screening visit and at all
follow-up visits, including the last visit of the study. Waist
circumference was measured at the randomization visit (Visit 2; Day
0), Visit 5 (Day 720) and the last visit of the study. Descriptive
statistics were presented by visit and treatment group for
baseline, post-treatment change from baseline, and the percent
change from baseline. Analysis methods for repeated measurements
were used to compare percent change from baseline between
treatments.
Additional prespecified efficacy endpoints and analyses of this
study are listed below. These endpoints and analyses were
exploratory in nature and were not included in the original testing
scheme: Time-to-event analyses as done for the primary analysis
were carried out at 1-year and 2-year landmarks for the ITT
Population; For the recurrent CV events analyses based on the
5-component MACE (CV death, non-fatal MI, non-fatal stroke,
unstable angina requiring hospitalization, or coronary
revascularization), a total CV event was performed using a Negative
Binomial Model analysis; An on treatment sensitivity analysis was
performed including primary events with onset up to 0 and 30 days
after permanent discontinuation of study drug; As done for the
primary analysis, time-to-event analyses at 1-year and 2-year
landmarks for the key secondary endpoints for the ITT Population;
An analysis of the following clinical events that are positively
adjudicated as tertiary endpoints for the ITT Population: Composite
of total mortality, or new CHF; Composite of CV death, or new CHF;
Sudden cardiac death; Peripheral artery disease (PAD); and Atrial
fibrillation, or atrial flutter. An analysis of the following as
tertiary endpoints for the ITT Population: Relationship between
on-treatment hsCRP and primary and key secondary endpoints; and
Relationship between on-treatment serum EPA and primary and key
secondary endpoints. To assess relationships between on-treatment
hsCRP and primary and key secondary endpoints, subgroup analyses as
done for the ITT population for patients grouped according to (1)
values greater or equal to or (2) less than 2 mg/dL at baseline and
at 2 years; To assess relationships between on-treatment serum EPA
and primary and key secondary endpoints, Kaplan Meier curves for
AMR101 patients grouped into tertiles based on values at year 1
compared with placebo patients; The following were added to the
subgroup analyses: Baseline HbA1c value (<6.5%, .gtoreq.6.5%);
Baseline PAD; and Baseline TG 150 mg/dL with HDL-C 40 mg/dL for
males and 50 mg/dL for females.
The following list presents additional pre-specified exploratory
efficacy analyses that are of particular interest to the general
clinical and scientific community that were also explored in this
study: Non-fatal myocardial infarction (MI) (including both
clinical manifestation and silent MI categorizations) for the ITT
Population; Evaluation of effect of time-weighted (or area under
the curve [AUC]) EPA data on the primary and key secondary
composite endpoints for the ITT Population; Sensitivity analyses on
primary and key secondary composite endpoints by excluding elective
coronary artery revascularizations if onset is <3 months post
randomization; and also excluding peri-procedural MIs for the ITT
Population; Two silent MI (SMI) sensitivity analyses on primary and
key secondary composite endpoints--ITT Population: Counting all
potential SMIs identified by CEC ECG reviewer, whether confirmed at
final ECG or not; and Counting only potential SMIs that have at
least one confirmatory ECG showing persistence of Q-waves (even if
not present at final ECG). Non-alcoholic fatty liver disease
(NAFLD) analyses using NAFLD Fibrosis Score (NFS), assessing--ITT
Population: Effect on primary and key secondary composite endpoints
by baseline NFS category; and Treatment effect on change from
baseline in NFS at 1 and 5 years. Individual and combined
on-treatment goal achievement of triglyceride (TG).ltoreq.150 mg/dL
and hsCRP 2 mg/L at 2 years, and end of study for the ITT
Population; Additional renal function (eGFR) analyses--ITT
Population: Primary and key secondary composite endpoints for
patients with baseline renal dysfunction [eGFR] 60 and <90
mL/min/1.73 m.sup.2; and Treatment effect on change from baseline
in renal function (eGFR) at 1 and 5 years. Sensitivity analyses on
primary and key secondary composite endpoints by excluding patients
with post-randomization LDL-C values >100 mg/dL; and another for
>70 mg/dL for the ITT Population; Analyses of hospitalization
data (pooled positively adjudicated unstable angina requiring
hospitalization, congestive heart failure [CHF] requiring
hospitalization, and cardiac arrhythmia requiring hospitalization)
for the ITT Population; Time from randomization to first
hospitalization; and Recurrent event analysis on hospitalizations.
Additional subgroup analyses (US versus Non-US) on the primary and
key secondary composite endpoints; also potentially other endpoints
for the ITT Population; Additional subgroup analyses for patients
with very high-risk cardiovascular disease (CVD) (defined as
recurrent cardiovascular [CV] events or CV events in more than one
vascular bed, i.e., polyvascular disease) on the primary and key
secondary composite endpoints; also potentially other endpoints for
the ITT Population; Sensitivity analyses for apo B to assess
whether subgroup(s) with apo B reductions from baseline beyond
certain threshold(s) have corresponding incremental reductions in
clinical endpoint events; Sensitivity analyses for myocardial
infarctions excluding peri-procedural MIs (Type 4a); Additional
analyses factoring for recency and number of prior MIs Sensitivity
analyses for stroke, factoring for patients with history of stroke
Sensitivity analyses for heart failure, factoring for patients with
history of heart failure Sensitivity analyses for endpoints
comprised of coronary revascularizations which exclude early
elective revascularizations (e.g., within 30-90 days
post-randomization) Subgroup analyses of primary (and potentially
key secondary) endpoint(s) among the following cohorts: High risk
patients with "the hypertriglyceridemic waist" (obese patients at
high CV risk); High risk subgroup defined by baseline hsTNT level
(and potentially by NT-proBNP from archived frozen samples); and
High TG/low LDL-C phenotypes; High-risk patients as defined by
their atherothrombotic risk score. Treatment effect on: Peripheral
arterial events (e.g., major adverse limb events [MALE]); and
Hypertension, using BP as a continuous variable. Using archived
frozen serum biosamples, additional analyses of fatty-acid levels
(and ratios), including baseline and on-treatment effects on EPA,
DHA, DPA, AA (and associated ratios) and relationships between
fatty-acid levels and cardiovascular outcomes; Relationship between
on-treatment fatty-acid levels; Baseline fatty-acid levels; and
Study medication compliance. Using archived frozen biosamples
(e.g., serum and whole blood); potential analyses of treatment
effects on biomarkers and genetic markers and associations with
outcomes, including but not limited to the following: LDL-P; RLP-C
(measured); LDL-TG; Ox-LDL; Galectin-3; Lp(a) at baseline, as a
predictor of CVD benefit; LpPLA2; HDL2, HDL3, apo A-I, apo A-III,
HDL-P, apo C-Ill (and apo C-III in apo-B containing proteins), apo
A-V, Apo E subtypes (2, 3, 4), IL-6, lipoprotein lipase (LPL); and
Analyses may include change (and percent change) from baseline,
on-treatment comparisons between treatment groups with testing as
predictors of CV risk. Exploratory analyses of differential
treatment effects for potential benefit (from adverse event
reports) of: Ophthalmologic changes (e.g., incidence of age-related
macular degeneration, progression of diabetic retinopathy);
Cognitive impairment; Erectile dysfunction; and Ischemic
cardiomyopathy (as indicated by hospitalization for CHF, ICD
placement etc.). Additional genetic bioassays including genes which
may relate to triglyceride, lipid metabolism, and CVD; and Effects
of potential mediators identified post hoc on primary/key secondary
outcome measures.
In this study, new onset diabetes was defined as Type 2 diabetes
newly diagnosed during the treatment/follow-up period (i.e.
patients with no history of diabetes at randomization). For
purposes of this study, a diagnosis of diabetes was made based on
the observation of: HbA.sub.1c.gtoreq.6.5%. The test was performed
in a laboratory using a method that is National Glycohemoglobin
Standardization Program (NGSP) certified and standardized to the
Diabetes Control and Complications Trial (DCCT) assay. In the
absence of unequivocal hyperglycemia, HbA.sub.1c.gtoreq.6.5% was
confirmed by repeat testing; Fasting plasma glucose (FPG) 2126
mg/dL (7.0 mmol/L). Fasting was defined as no caloric intake for at
least 8 hr. In the absence of unequivocal hyperglycemia, FPG
.gtoreq.126 mg/dL (7.0 mmol/L) was confirmed by repeat testing;
2-hr plasma glucose .gtoreq.200 mg/dL (11.1 mmol/L) during an Oral
Glucose Tolerance Test (OGTT). The test was performed as described
by the World Health Organization, using a glucose load containing
the equivalent of 75 g anhydrous glucose dissolved in water. In the
absence of unequivocal hyperglycemia, 2-hr plasma glucose
.gtoreq.200 mg/dL (11.1 mmol/L) during an Oral Glucose Tolerance
Test (OGTT) were confirmed by repeat testing; and/or In a patient
with classic symptoms of hyperglycemia or hyperglycemic crisis, a
random plasma glucose 200 mg/dL (11.1 mmol/L).
In the absence of unequivocal hyperglycemia, the first three
criteria were confirmed by repeat testing.
Exploratory Subgroup Analyses:
Analyses of the effects that patients off study drug and withdrawn
from study have on the primary endpoint were performed. Subgroup
analyses of the primary and key secondary endpoints were performed
as described for the primary endpoint. For each subgroup,
Kaplan-Meier estimates, the log-rank test stratified by
stratification factors used at randomization (except where the
subgroup was a stratification factor), and HRs and CIs from the Cox
proportional hazards model as specified for the primary efficacy
endpoint, were summarized by treatment group. Demographic, disease,
treatment, and baseline lipid and lipoproteins parameters were
explored.
Demographic parameters included: Gender; age at baseline (<65
years and 65 years); race (white and nonwhite, or any other subset
with at least 10% of the total number of patients); geographical
region (Westernized, Eastern European, and Asia Pacific countries);
and baseline ezetimibe use (yes/no).
Disease parameters included: CV risk category; the presence/absence
of diabetes at baseline; and renal dysfunction at baseline
(estimated glomerular filtration rate [eGFR]<60 mL/min/1.73
m.sup.2) using the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) equation as follows: eGFR=141.times.min
(S.sub.cr/.kappa.,1).sup..alpha..times.max(S.sub.cr/.kappa.,1).sup.-1.209-
.times.0.993.sup.Age.times.1.018 [if female].times.1.159 [if black]
Where: S.sub.cr is serum creatinine in mg/dL, K is 0.7 for females
and 0.9 for males, .alpha. is -0.329 for females and -0.411 for
males, min indicates the minimum of S.sub.cr/.kappa. or 1, and max
indicates the maximum of S.sub.cr/.kappa. or 1.
Treatment Parameters included: Statin intensity at baseline (statin
type and regimen); and statin intensity categories as defined in
ACC/AHA Cholesterol Guidelines (Stone 2013) and patient's 10-year
CV Risk Score (Goff 2013).
Baseline Lipid and Lipoprotein Parameter included: LDL-C (by
tertile); HDL-C (by tertile, and tertile by gender); TG (by
tertile, and tertile by gender); RLP-C (by tertile); TG .gtoreq.150
mg/dL and TG <150 mg/dL; TG .gtoreq.200 mg/dL and TG <200
mg/dL; TG .gtoreq.median, TG <median; combined highest tertile
for TG and lowest tertile for HDL-C; gender-specific highest
tertile for TG and lowest tertile for HDL-C; TG 200 mg/dL with
HDL-C 35 mg/dL; hsCRP (53 mg/L and >3 mg/L) and by gender; hsCRP
(52 mg/L and >2 mg/L) and by gender; Apo B (by tertile);
non-HDL-C (by tertile); baseline hemoglobin A1c (Hb1c) value
(<6.5%, .gtoreq.6.5%); baseline PAD; and baseline TG levels 150
mg/dL with high-density lipoprotein cholesterol (HDL-C)
levels.ltoreq.40 mg/dL for males and .ltoreq.50 mg/dL for
females.
A Cox proportional hazard (PH) model as mentioned above but
additionally with baseline TG as a covariate were fitted to the
data at each interim. Diagnostic plots for the PH assumption were
evaluated. The consistency of the treatment effects in subgroups
was assessed for the primary and key secondary efficacy endpoints.
For each subgroup variable, a Cox PH model with terms for
treatment, stratification factors (with the exception of those
subgroup variables related to the stratification factors, i.e., CV
risk category), subgroup, and treatment-by-subgroup interaction
were performed. The main treatment effect was tested with this
model. P-values for testing the interaction terms <0.15 were
considered significant. Results were presented in a Forest
plot.
Subgroup analyses of the primary and key secondary endpoints were
performed as described for the primary endpoint. For each subgroup,
Kaplan-Meier estimates, the log-rank test stratified by
stratification factors used at randomization (except where the
subgroup was a stratification factor), and HRs and CIs from the Cox
proportional hazards model as specified for the primary efficacy
endpoint, were summarized by treatment group. All subgroup analyses
were conducted for the ITT, mITT and PP populations.
Interim Efficacy Analysis:
Two interim analyses were planned for the primary efficacy endpoint
using adjudicated events when approximately 60% (967 events) and
approximately 80% (1290 events) of the total number of primary
endpoint events planned (1612) was reached. The planned interim
analyses were based on a group-sequential design.
The interim results of the study were monitored by an independent
Data Monitoring Committee (DMC). The analyses were performed by the
independent statistical team who was unblinded to the treatment
assignment and reported only to the DMC. If the study was
terminated early following interim analysis, patients were notified
promptly and brought in for their final close-out visit, and the
final analyses of efficacy and safety included all data through
their final visit. All suspected events were adjudicated in a
blinded manner by the CEC. The time to event was calculated as the
time from randomization to the onset date of the event (as
determined by the CEC). Patients who do not experience any of the
above events at the time of data cutoff for the interim but were
still in the trial were considered censored at the time of their
last regular contact before the interim data cutoff.
The alpha-levels for the two protocol prespecified interim analyses
and the final analysis are based on a group sequential design (GSD)
with O'Brien-Fleming boundaries generated using the Lan-DeMets
alpha spending function. The one-sided alpha-levels and boundaries
based on a Z-test and the achieved p-values for each of the two
interim analyses and the final analysis are given in Table 10.
TABLE-US-00011 TABLE 10 Group Sequential P-Values Boundaries
According to Two Actual Interim Analyses Information Fractions
Efficacy Efficacy Infor- Boundary Boundary Achieved Anal- No. of
mation (1-sided (2-sided P-value Look ysis Events Fraction
.alpha.-level) .alpha.-level) (2-sided) 1 IA#1 953 59.3% 0.00356
0.0071 0.0000463 2 IA#2 1218 75.8% 0.00885 0.0177 0.00000082 3
Final 1606 100% 0.02186 0.0437 0.00000001
Analysis of Safety:
All analyses of safety were conducted on the safety population,
which was defined as all randomized patients. The safety assessment
was based on the frequency of adverse events, physical exams, vital
signs and safety laboratory tests. AEs with new onset during the
study between the initiation of study drug and 30 days after the
last dose of study drug for each patient was considered
treatment-emergent (TEAEs). This included any AE with onset prior
to initiation of study drug and increased severity after the
treatment initiation.
Treatment-emergent adverse events were summarized by system organ
class and preferred term, and by treatment. This included overall
incidence rates (regardless of severity and relationship to study
drug), and incidence rates for moderate or severe adverse events. A
summary of SAEs and adverse events leading to early discontinuation
(for 30 days) were presented through data listings. Patients who
restarted study drug were included in the summary of AEs leading to
discontinuation. Safety laboratory tests and vital signs were
summarized by post-treatment change from baseline for each of the
parameters using descriptive statistics by treatment group. Those
patients with significant laboratory abnormalities were identified
in data listings. Additional safety parameters were summarized in
data listings.
In addition to the treatment-emergent adverse events analyses,
analyses on all AEs (serious and non-serious) and all serious AEs
were performed.
All AEs included: treatment-emergent adverse event (TEAE) by high
level group term (HLGT); TEAE by high level term (HLT); and TEAE by
system organ class (SOC), HLGT, HLT, and preferred term (PT)
(4-level table).
All SAEs included: treatment emergent SAE by HLGT; treatment
emergent SAE by HLT; and treatment emergent SAE by SOC, HLGT, HLT,
and PT (4-level table).
Clinical Laboratory Evaluation
The criteria for potentially clinically significant (PCS)
laboratory values are provided in Table 11 and Table 12. A
treatment-emergent PCS high value at any time was defined as a
change from a value less than or equal to the upper reference limit
at baseline to a PCS high value at any post-baseline measurement. A
treatment-emergent PCS low value at any time was defined as a
change from a value greater than or equal to the lower reference
limit at baseline to a PCS low value at any post-baseline
measurement. Number (%) of patients with any post-baseline PCS
laboratory values was summarized by treatment group. A listing of
patients with PCS laboratory values at any time, i.e., baseline or
at any post-baseline visit, were included.
TABLE-US-00012 TABLE 11 Potentially Clinically Significant
Chemistry Values Parameter PCS Low PCS High Albumin .ltoreq.3.3
g/dL .gtoreq.5.8 g/dL Alkaline Not Applicable (N/A) >1x ULN to
2x ULN Phosphate >2x ULN to 3x ULN >3x ULN ALT N/A >1x ULN
to 2x ULN >2x ULN to 3x ULN >3x ULN AST N/A >1x ULN to 2x
ULN >2x ULN to 3x ULN >3x ULN Bilirubin N/A >1x ULN to 2x
ULN >2x ULN to 3x ULN >3x ULN ALT + Bilirubin N/A >3x ULN
+ 2x ULN (Bilirubin) AST + Bilirubin N/A >3x ULN + 2x ULN
(Bilirubin) Calcium .ltoreq.7 mg/dL .gtoreq.11 g/dL .ltoreq.12
mg/dL Chloride <70 mmol/L >120 mmol/L Creatinine <0.5
mg/dL (Female) >1.6 mg/dL (Female) <0.65 mg/dL (Male) >2.0
mg/dL (Male); .gtoreq.50% increase from baseline Creatine Kinase
<30 U/L (Female) >1x ULN to 5x ULN <0.55 U/L (Male) >5x
ULN to 10x ULN >10x ULN Glucose (fasting) .ltoreq.36 mg/dL;
.gtoreq.126 mg/dL; .ltoreq.70 mg/dL .gtoreq.130 mg/dL Potassium (K)
.ltoreq.3.0 mEq/L .gtoreq.150 mEq/L Total Protein <5.0 g/dL
.gtoreq.9.5 g/dL Urea Nitrogen N/A .gtoreq.31 mg/dL (BUN) Uric Acid
<1.9 mg/dL (Female) >7.5 mg/dL (Female) <2.5 mg/dL (Male)
>8 mg/dL (Male)
TABLE-US-00013 TABLE 12 Potentially Clinically Significant
Hematology Values Parameter PCS Low PCS High Red Blood Cell <3.5
.times. 10.sup.6/.mu.L (Female) >3.5 .times. 10.sup.6/.mu.L
(Female) (RBC) <3.8 .times. 10.sup.6/.mu.L (Male) >3.8
.times. 10.sup.6/.mu.L (Male) Hemoglobin <10.0 g/dL (Female)
> (Hgb) <10.0 g/dL (Male) > Hematocrit (Hct) <37%
(Female) > <42% (Male) > White Blood Cells <1.5 .times.
10.sup.3/.mu.L N/A (WBC) White Cell Segmented Segmented
Differential neutrophils <50% neutrophils >70% Lymphocytes
<30% Lymphocytes >45% Monocytes N/A Monocytes >6%
Basophils N/A Basophils >1% Eosinophils N/A Eosinophils >3%
Platelet Count <100 .times. 10.sup.3/.mu.L >500 .times.
10.sup.3/.mu.L
Drug-Induced Liver Injury (DILI)
DILI cases were investigated through the following analyses: A
graph of distribution of peak values of alanine aminotransferase
(ALT) versus peak values of total bilirubin (TBL) during the
treatment period was prepared, using a logarithmic scale. In the
graph, for each patient, the peak TBL times the Upper Limit of
Normal (ULN) were plotted against the peak ALT times the ULN, where
the peak TBL and peak ALT may or may not have happened on the same
day of liver testing. The graph was divided into 4 quadrants with a
vertical line corresponding to 3.times.ULN for ALT and a horizontal
line corresponding to 2.times.ULN for TBL. The upper right quadrant
was referred to as the potential Hy's Law quadrant, including
potentially DILI cases. A similar graph was plotted with respect to
aspartate aminotransferase (AST). The individual patient profile of
liver function tests (ALT, AST, alkaline phosphatase [ALP] and TBL)
over time was provided through a graph for all patients with peak
value of ALT >3.times.ULN and peak value of TBL >2.times.ULN
during the treatment period. Number (%) of patients was provided
for the following: ALT or AST >3.times.ULN; ALT or AST
>3.times.ULN and TBL >2.times.ULN; and ALT or AST
>3.times.ULN and TBL >2.times.ULN, and ALP <2.times.ULN.
Study Design
This was a Phase 3b, multi-center, multi-national, prospective,
randomized, double-blind, placebo-controlled, parallel-group study.
This was also an event-driven trial comparing the effect of AMR101
vs. placebo in terms of the composite endpoint listed above as the
primary endpoint. The placebo contained mineral oil to mimic the
color and consistency of icosapent ethyl in AMR101 and was
administered in the same capsule fill volume and count as the
AMR101. The study accrued a total of 1612 efficacy endpoint events
with two planned interim analyses when approximately 967 (60%) and
1290 (80%) of the events had been adjudicated. The study included
patients with established CVD (CV Risk Category 1) and patients
.gtoreq.50 years old with diabetes and at least one additional risk
factor for CVD but with CVD not established (CV Risk Category 2).
Randomization was stratified by cardiovascular risk stratum which
included the secondary-prevention cohort (i.e., CV Risk Category 1)
or primary-prevention cohort (i.e., CV Risk Category 2), with the
primary prevention cohort capped at 30% of enrolment, use or no use
of ezetimibe, and by geographical region. Details of the study
design are shown in FIG. 1.
Sample size calculation was based on the assumption of constant
hazard, asymmetric recruitment rate overtime and without factoring
for dropouts. A risk reduction corresponding to a HR of 0.85
(AMRI01 vs. placebo) was assumed. 1612 events were required to
detect this HR with approximately 90% power with one-sided
alpha-level at 2.5% and with two interim analyses. The operating
characteristics of this design were identical to those of a
corresponding group sequential design with a two-sided alpha level
of 0.05.
The recruitment period was assumed to be 4.2 years with 20%
recruitment in the first year, 40% in the second year, 20% in the
third year, 19% in the fourth year and the remaining 1% in the last
0.2 years. The estimated maximum study duration was 6.5 years
unless the trial was terminated early for efficacy or safety
issues. A one-year event rate of 5.2% (hazard=0.053) in the control
arm was also assumed. Under these assumptions the number of
patients enrolled was N=7990.
Since this was an events-driven trial, the `sample size` was the
number of events rather than the number of patients. The number of
events that occurred depends primarily on three factors: how many
patients were enrolled; the combined group event rate; and how long
the patients were followed. Because of the difficulty in predicting
the combined event rate, the Sponsor monitored the event rate as
the trial progressed. If the combined event rate was less than
anticipated, either increasing the number of patients, extending
the length of follow-up, or a balance of adjusting both factors was
necessary to achieve the sample size of 1612 events.
At completion of study enrollment, the actual number of patients
randomized may have varied from the target number (either original
or revised) as a result of the inherent lag between the date the
last patient started screening and the date the last patient was
randomized.
Completion of Study
The end of the study was at the time the last patient-last visited
of the follow-up period of the study. The IRB and IEC were notified
about the end of the study according to country-specific regulatory
requirements.
Standardized Definitions for the Cardiovascular Trial Endpoint
Events
In assessing patients in this clinical trial, the follow
definitions were used:
Definition of Cardiovascular Death:
Cardiovascular death includes death resulting from an acute
myocardial infarction, sudden cardiac death, death due to
congestive heart failure (CHF), death due to stroke, death due to
cardiovascular (CV) procedures, death due to CV hemorrhage, and
death due to other cardiovascular causes.
Death Due to Acute Myocardial Infarction:
refers to a death by any mechanism (e.g., arrhythmia, CHF) within
30 days after a MI related to the immediate consequences of the MI,
such as progressive CHF or recalcitrant arrhythmia. Mortal events
that occur after a "break" (e.g., a CHF and arrhythmia-free period
of at least a week) should be classified as CV or non-CV death, and
if classified as a CV death, should be attributed to the immediate
cause, even though the MI may have increased the risk of that event
(e.g., the risk of arrhythmic death is increased for many months
after an acute MI). Acute MI should be verified to the extent
possible by the diagnostic criteria outlined for acute MI (see
Definition of MI) or by autopsy findings showing recent MI or
recent coronary thrombosis. Death resulting from a procedure to
treat a MI (percutaneous coronary intervention (PCI), coronary
artery bypass graft surgery (CABG)), or to treat a complication
resulting from MI, should also be considered death due to acute MI.
Death resulting from an elective coronary procedure to treat
myocardial ischemia (i.e., chronic stable angina) or death due to a
MI that occurs as a direct consequence of a CV
investigation/procedure/operation should be considered as a death
due to a CV procedure.
Sudden Cardiac Death:
refers to a death that occurs unexpectedly, not within 30 days of
an acute MI, and includes the following deaths: death witnessed and
instantaneous without new or worsening symptoms; death witnessed
within 60 minutes of the onset of new or worsening cardiac
symptoms, unless the symptoms suggest an acute MI; death witnessed
and attributed to an identified arrhythmia (e.g., captured on an
electrocardiographic (ECG) recording, witnessed on a monitor, or
unwitnessed but found on implantable cardioverter-defibrillator
review); death after unsuccessful resuscitation from cardiac
arrest; death after successful resuscitation from cardiac arrest
and without identification of a non-cardiac etiology; and/or
unwitnessed death without other cause of death (information
regarding the patient's clinical status preceding death should be
provided, if available)
General Considerations for Sudden Cardiac Death: A subject seen
alive and clinically stable 12-24 hours prior to being found dead
without any evidence or information of a specific cause of death
should be classified as "sudden cardiac death." Deaths for which
there is no information beyond "patient found dead at home" are
classified as "death due to other cardiovascular causes". (See
Definition of Undetermined Cause of Death, for full details
below).
Death Due to Congestive Heart Failure:
refers to a death in association with clinically worsening symptoms
and/or signs of heart failure (See Definition of Heart Failure
Event, for full details below). Deaths due to heart failure can
have various etiologies, including single or recurrent myocardial
infarctions, ischemic or non-ischemic cardiomyopathy, hypertension,
or valvular disease.
Death Due to Stroke:
refers to death after a stroke that is either a direct consequence
of the stroke or a complication of the stroke. Acute stroke should
be verified to the extent possible by the diagnostic criteria
outlined for stroke (See Definition of Transient Ischemic Attack
and Stroke, for full details below).
Death Due to Cardiovascular Procedures:
refers to death caused by the immediate complications of a cardiac
procedure.
Death Due to Cardiovascular Hemorrhage:
refers to death related to hemorrhage such as a non-stroke
intracranial hemorrhage (see Definition of Transient Ischemic
Attack and Stroke, for full details below), non-procedural or
non-traumatic vascular rupture (e.g., aortic aneurysm), or
hemorrhage causing cardiac tamponade.
Death Due to Other Cardiovascular Causes:
refers to a CV death not included in the above categories (e.g.,
pulmonary embolism or peripheral arterial disease).
Definition of Non-Cardiovascular Death:
Non-cardiovascular death is defined as any death that is not
thought to be due to a cardiovascular cause. The following is a
suggested list of non-cardiovascular causes of death for this
trial. Non-malignant, Non-cardiovascular Death: Pulmonary; Renal;
Gastrointestinal; Hepatobiliary; Pancreatic; Infection (includes
sepsis) Non-infectious (e.g., systemic inflammatory response
syndrome (SIRS)); Hemorrhage that is neither cardiovascular
bleeding nor a stroke; Accidental (e.g., physical accidents or drug
overdoses) or trauma; Suicide; and/or Prescription Drug Error
(e.g., prescribed drug overdose, use of inappropriate drug, or
drug-drug interaction); and Neurological process that is not a
stroke or hemorrhage. Malignancy: Malignancy is coded as cause of
death, if: Death results directly from the cancer; or Death results
from a concurrent illness that could be a consequence of a cancer;
or Death results from withdrawal of other therapies because of
concerns relating to the poor prognosis associated with the cancer;
and Death results from an illness that is not a consequence of a
cancer.
Cancer deaths may arise from cancers that were present prior to
randomization or which developed subsequently. It may be helpful to
distinguish these two scenarios (i.e. worsening of prior
malignancy; new malignancy). Suggested categorization includes the
following organ systems; Lung/larynx, breast, leukemia/lymphoma,
upper GI, melanoma, central nervous system, colon/rectum, renal,
bladder, prostate, other/unspecified, or unknown.
Definition of Undetermined Cause of Death:
refers to a death not attributable to one of the above categories
of cardiovascular death or to a non-cardiovascular cause. The
inability to classify the cause of death is generally due to lack
of information (e.g., the only available information is "patient
died") or when there is insufficient supporting information or
detail to assign the cause of death. In this trial, when a cause of
death was not readily apparent (e.g., found dead at home), the
cause was assumed to be cardiovascular in origin, unless one of the
following two scenarios occur: there is no information or data
available regarding the circumstances of death other than that a
death has occurred; or the available data are conflicting regarding
whether the death was cardiovascular or non-cardiovascular.
Definition of Myocardial Infarction:
The term myocardial infarction (MI) is used when there is evidence
of myocardial necrosis in a clinical setting consistent with
myocardial ischemia. In general, the diagnosis of MI requires the
combination of: evidence of myocardial necrosis (either changes in
cardiac biomarkers or postmortem pathological findings); and
supporting information derived from the clinical presentation,
electrocardiographic changes, or the results of myocardial or
coronary artery imaging.
The totality of the clinical, electrocardiographic, and cardiac
biomarker information should be considered to determine whether or
not a MI has occurred. Specifically, timing and trends in cardiac
biomarkers and electrocardiographic information require careful
analysis. The adjudication of MI should also take into account the
clinical setting in which the event occurs. MI may be adjudicated
for an event that has characteristics of a MI, but which does not
meet the strict definition because biomarker or
electrocardiographic results are not available.
The Criteria for myocardial infarction include clinical
presentation, biomarker evaluation, and ECG changes.
Clinical Presentation:
The clinical presentation is consistent with diagnosis of
myocardial ischemia and infarction. Other findings that might
support the diagnosis of MI should be take into account because a
number of conditions are associated with elevations in cardiac
biomarkers (e.g., trauma, surgery, pacing, ablation, congestive
heart failure, hypertrophic cardiomyopathy, pulmonary embolism,
severe pulmonary hypertension, stroke or subarachnoid hemorrhage,
infiltrative and inflammatory disorders of cardiac muscle, drug
toxicity, burns, critical illness, extreme exertion, and chronic
kidney disease). Supporting information can also be considered from
myocardial imaging and coronary imaging. The totality of the data
may help differentiate acute MI from the background disease
process.
Biomarker Evaluation:
For cardiac biomarkers, laboratories should report an upper
reference limit (URL). If the 99th percentile of the upper
reference limit (URL) from the respective laboratory performing the
assay is not available, then the URL for myocardial necrosis from
the laboratory should be used. If the 99th percentile of the URL or
the URL for myocardial necrosis is not available, the MI decision
limit for the particular laboratory should be used as the URL.
Laboratories can also report both the 99th percentile of the upper
reference limit and the MI decision limit. Reference limits from
the laboratory performing the assay are preferred over the
manufacturer's listed reference limits in an assay's instructions
for use. CK-MB and troponin are preferred, but CK may be used in
the absence of CK-MB and troponin. For MI subtypes, different
biomarker elevations for CK, CK-MB, or troponin were required. The
specific criteria were referenced to the URL. In this study,
patients may present acutely to hospitals which are not
participating sites, it is not practical to stipulate the use of a
single biomarker or assay, and the locally available results are to
be used as the basis for adjudication. Since the prognostic
significance of different types of myocardial infarctions (e.g.,
periprocedural myocardial infarction versus spontaneous myocardial
infarction) may be different, considerations evaluating outcomes
for these subsets of patients separately were made.
Ecg Changes:
ECG changes can be used to support or confirm a MI. Supporting
evidence may be ischemic changes and confirmatory information may
be new Q waves.
Criteria for acute myocardial ischemia (in absence of left
ventricular hypertrophy (LVH) and left bundle branch block (LBBB))
include: ST elevation: New ST elevation at the J point in two
anatomically contiguous leads with the cut-off points: .gtoreq.0.2
mV in men (>0.25 mV in men <40 years) or .gtoreq.0.15 mV in
women in leads V2-V3 and/or .gtoreq.0.1 mV in other leads. ST
depression and T-wave changes new horizontal or down-sloping ST
depression .gtoreq.0.05 mV in two contiguous leads; and/or new T
inversion .gtoreq.0.1 mV in two contiguous leads.
The above ECG criteria illustrate patterns consistent with
myocardial ischemia. In patients with abnormal biomarkers, it is
recognized that lesser ECG abnormalities may represent an ischemic
response and may be accepted under the category of abnormal ECG
findings.
Criteria for pathological Q-wave include: any Q-wave in leads V2-V3
.gtoreq.0.02 seconds or QS complex in leads V2 and V3; Q-wave
.gtoreq.0.03 seconds and .gtoreq.0.1 mV deep or QS complex in leads
I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead
grouping (I, aVL, V6; V4-V6; II, III, and aVF); and R-wave 0.04 s
in V1-V2 and R/S ratio >1 with a concordant positive T-wave in
the absence of a conduction defect.
The same criteria are used for supplemental leads V7-V9, and for
the Cabrera frontal plane lead grouping.
Criteria for Prior Myocardial Infarction include: pathological
Q-waves, as defined above; and R-wave .gtoreq.0.04 seconds in V1-V2
and R/S.gtoreq.1 with a concordant positive T-wave in the absence
of a conduction defect.
Myocardial Infarction Subtypes:
Several MI subtypes are commonly reported in clinical
investigations and each is defined below:
1. Spontaneous MI:
Detection of rise and/or fall of cardiac biomarkers with at least
one value above the URL with at least one of the following:
Clinical presentation consistent with ischemia; ECG evidence of
acute myocardial ischemia; New pathological Q waves; Imaging
evidence of new loss of viable myocardium or new regional wall
motion abnormality; and/or Autopsy evidence of acute MI If
biomarkers are elevated from a prior infarction, then a spontaneous
myocardial infarction is defined as one of the following: Clinical
presentation consistent with ischemia; ECG evidence of acute
myocardial ischemia; New pathological Q waves; Imaging evidence of
new loss of viable myocardium or new regional wall motion
abnormality; and/or Autopsy evidence of acute MI; and Both of the
Following: Evidence that cardiac biomarker values were decreasing
(e.g., two samples 3-6 hours apart) prior to the suspected MI
(note: If biomarkers are increasing or peak is not reached, then a
definite diagnosis of recurrent MI is generally not possible); and
.gtoreq.20% increase (and >URL) in troponin or CK-MB between a
measurement made at the time of the initial presentation and a
further sample taken 3-6 hours later. 2. Percutaneous Coronary
Intervention-Related Myocardial Infarction: is defined by any of
the following criteria. MI associated with and occurring within 48
hours of PCI, with elevation of cardiac biomarker values to
>5.times.99.sup.th percentile of the URL in patients with normal
baseline values (.ltoreq.99.sup.th percentile URL), or a rise of
[cardiac biomarker] values 20% if baseline values are elevated and
are stable or falling. This classification also requires at least 1
of the following: Symptoms suggestive of myocardial ischemia (i.e.,
prolonged ischemia .gtoreq.20 min); New ischemic changes on ECG or
new LBBB; Angiographic loss of patency of a major coronary artery
or a side branch or persistent slow flow or no flow or
embolization; and/or Imaging evidence of new loss of viable
myocardium or new regional wall motion abnormality. 3. Coronary
Artery Bypass Grafting-Related (CABG) Myocardial Infarction: is
defined by the following criteria. Symptoms of cardiac ischemia
were not required and data was collected in such a way that
analyses using .gtoreq.20% or .gtoreq.50% could both be performed.
Biomarker elevations within 48 hours of CABG: Troponin or CK-MB
(preferred) >10.times.99.sup.th percentile of the URL; and No
evidence that cardiac biomarkers were elevated prior to the
procedure; or Both of the following are true: .gtoreq.50% increase
in the cardiac biomarker result; and Evidence that cardiac
biomarker values were decreasing (e.g., two samples 3-6 hours
apart) prior to the suspected MI; and One of the following are
true: New pathological Q-waves persistent through 30 days; New
persistent non-rate-related LBBB; Angiographically documented new
graft or native coronary artery occlusion Other complication in the
operating room resulting in loss of myocardium; or Imaging evidence
of new loss of viable myocardium. Autopsy evidence of acute MI. 4.
Silent Myocardial Infarction: is defined by the following: No
evidence of acute myocardial infarction; and Any one of the
following criteria: New pathological Q-waves. A confirmatory ECG is
recommended if there have been no clinical symptoms or history of
myocardial infarction; Imaging evidence of a region of loss of
viable myocardium that is thinned and fails to contract, in the
absence of a non-ischemic cause; and/or Autopsy evidence of a
healed or healing MI.
In the case of evanescent 0 waves, the last ECG determines whether
a silent infarction has occurred.
Sub-Classification of Myocardial Infarction:
The universal MI definition includes clinical classification of
different types of MI, electrocardiographic features, and by
biomarker evaluation, with the definition of each provided
below.
Clinical Classification of Different Types of Myocardial Infarction
include the following: Type 1: Spontaneous myocardial infarction
related to ischemia due to a primary coronary event such as plaque
erosion and/or rupture, fissuring, or dissection; Type 2:
Myocardial infarction secondary to ischemia due to either increased
oxygen demand or decreased supply, e.g., coronary artery spasm,
coronary embolism, anemia, arrhythmias, hypertension, or
hypotension; Type 3: Sudden unexpected cardiac death, including
cardiac arrest, often with symptoms suggestive of myocardial
ischemia, accompanied by presumably new ST elevation, or new LBBB,
or evidence of fresh thrombus in a coronary artery by angiography
and/or at autopsy, but death occurring before blood samples could
be obtained, or at a time before the appearance of cardiac
biomarkers in the blood; Type 4a: Myocardial infarction associated
with Percutaneous Coronary Intervention (PCI); Type 4b: Myocardial
infarction associated with stent thrombosis as documented by
angiography or at autopsy; Type 4c: Myocardial infarction
associated with stent restenosis as detected by angiography or at
autopsy; and Type 5: Myocardial infarction associated with
CABG.
By Electrocardiographic Features include: ST-Elevation MI (STEMI).
The additional categories of STEMI include: Q wave, non-Q-wave, or
unknown (no ECG or ECG non-interpretable); Non-ST-Elevation MI
(NSTEMI). The additional categories NSTEMI may include: Q wave,
non-Q-wave, or unknown (no ECG or ECG non-interpretable); and
Unknown (no ECG or ECG not interpretable).
All events adjudicated as MI were classified as STEMI, NSTEMI, or
Unknown; however, it is acknowledged that a significant proportion
of periprocedural (PCI or CABG) events may have missing, inadequate
or uninterpretable ECG documentation.
By Biomarker Elevation (per Universal MI Definition): The magnitude
of cardiac biomarker elevation can be calculated as a ratio of the
peak biomarker value divided by the 99th percentile URL. The
biomarker elevation can be provided for various MI subtypes.
Definition of Hospitalize of Unstable Angina:
Unstable angina requiring hospitalization is defined as: Ischemic
discomfort (angina, or symptoms thought to be equivalent)
.gtoreq.10 minutes in duration occurring at rest or in an
accelerating pattern with frequent episodes associated with
progressively decreased exercise capacity; Prompting an unscheduled
hospitalization within 24 hours of the most recent symptoms.
Hospitalization is defined as an admission to an inpatient unit or
a visit to an emergency department that results in at least a
24-hour stay (or a date change if the time of admission/discharge
is not available); and At least one of the following: New or
worsening ST or T wave changes on resting ECG (in absence of
confounders, such as LBBB or LVH); Transient ST elevation (duration
<20 minutes): New ST elevation at the J point in two
anatomically contiguous leads with the cut-off points: .gtoreq.0.2
mV in men (.gtoreq.0.25 mV in men <40 years) or .gtoreq.0.15 mV
in women in leads V2-V3 and/or 0.1 mV in other leads ST depression
and T-wave changes: New horizontal or down-sloping ST depression
.gtoreq.0.05 mV in two contiguous leads; and/or new T inversion
.gtoreq.0.1 mV in two contiguous leads. Definite evidence of
inducible myocardial ischemia as demonstrated by: An early positive
exercise stress test, defined as ST elevation or .gtoreq.2 mm ST
depression prior to 5 mets; or at least one of the following:
stress echocardiography (reversible wall motion abnormality);
myocardial scintigraphy (reversible perfusion defect); or MRI
(myocardial perfusion deficit under pharmacologic stress.
Angiographic evidence of new or worse .gtoreq.70% lesion and/or
thrombus in an epicardial coronary artery that is believed to be
responsible for the myocardial ischemic symptoms/signs; and Need
for coronary revascularization procedure (PCI or CABG) for the
presumed culprit lesion(s). This criterion would be fulfilled if
revascularization was undertaken during the unscheduled
hospitalization, or subsequent to transfer to another institution
without interceding home discharge; Negative cardiac biomarkers and
no evidence of acute MI.
General Considerations include:
Escalation of pharmacotherapy for ischemia, such as intravenous
nitrates or increasing dosages of .beta.-blockers, should be
considered supportive of the diagnosis of unstable angina. However,
a typical presentation and admission to the hospital with
escalation of pharmacotherapy, without any of the additional
findings listed under category 3, would be insufficient alone to
support classification as hospitalization for unstable angina.
If subjects were admitted with suspected unstable angina, and
subsequent testing revealed a noncardiac or non-ischemic etiology,
this event should not have been recorded as hospitalization for
unstable angina. Potential ischemic events meeting the criteria for
myocardial infarction should not have been adjudicated as unstable
angina.
Planned hospitalization or re-hospitalization for performance of an
elective revascularization in patients who did not fulfill the
criteria for unstable angina should not have been considered a
hospitalization for unstable angina. For example: hospitalization
of a patient with stable exertional angina for coronary angiography
and PCI that is prompted by a positive outpatient stress test
should not be considered hospitalization for unstable angina; or
re-hospitalization of a patient meeting the criteria for unstable
angina who was stabilized, discharged, and subsequently readmitted
for revascularization, does not constitute a second hospitalization
for unstable angina.
A patient who underwent an elective catheterization where
incidental coronary artery disease was found and who subsequently
underwent coronary revascularization was not be considered as
meeting the hospitalization for unstable angina endpoint.
Transient Ischemic Attack:
Transient ischemic attack (TIA) is defined as a transient episode
(<24 hours) of neurological dysfunction caused by focal brain,
spinal cord, or retinal ischemia, without acute infarction.
Stroke:
Stroke is defined as an acute episode of neurological dysfunction
caused by focal or global brain, spinal cord, or retinal vascular
injury.
Ischemic Stroke:
Ischemic stroke is defined as an acute episode of focal cerebral,
spinal, or retinal dysfunction caused by an infarction of central
nervous system tissue. Hemorrhage may be a consequence of ischemic
stroke. In this situation, the stroke is an ischemic stroke with
hemorrhagic transformation and not a hemorrhagic stroke.
Hemorrhagic Stroke:
Hemorrhagic stroke is defined as an acute episode of focal or
global cerebral or spinal dysfunction caused by a nontraumatic
intraparenchymal, intraventricular, or subarachnoid hemorrhage.
However, microhemorrhages seen on T2-weighted MRI imaging, subdural
and epidural hemorrhages are not considered hemorrhagic
strokes.
Undetermined Stroke:
Undetermined stroke is defined as an acute episode of focal or
global neurological dysfunction caused by presumed brain, spinal
cord, or retinal vascular injury as a result of hemorrhage or
infarction but with insufficient information to allow
categorization as ischemic or hemorrhagic.
Stroke Disability:
Stroke disability should be measured by a reliable and valid scale
in all cases, typically at each visit and 90 days after the event.
For example, the modified Rankin Scale show below in Table 13 may
be used to address this requirement:
TABLE-US-00014 TABLE 13 Rankin Scaled Used to Assess Stroke
Disability in Patients Scale Disability 0 No symptoms at all. 1 No
significant disability despite symptoms; able to carry out all
usual duties and activities. 2 Slight disability, unable to perform
all previous activities but able to look after own affairs without
assistance. 3 Moderate disability; requiring some help but able to
walk without assistance. 4 Moderately severe disability, unable to
walk without assistance and unable to attend to own bodily needs
without assistance. 5 Severe disability, bedridden, incontinent,
and requiring constant nursing and attention. 6 Dead
Additional Considerations: Evidence of vascular central nervous
system injury without recognized neurological dysfunction may be
observed. Examples include micro-hemorrhage, silent infarction, and
silent hemorrhage. Subdural hematomas are intracranial hemorrhagic
events and not strokes. The distinction between a Transient
Ischemic Attack and an Ischemic Stroke is the presence of
Infarction. Persistence of symptoms is an acceptable indicator of
acute infarction.
Definition of Heart Failure Event:
is defined as an event that meets all of the following criteria:
The patient is admitted to the hospital with a primary diagnosis of
HF; The patient's length-of-stay in hospital extends for at least
24 hours (or a change in calendar date if the hospital admission
and discharge times are unavailable); The patient exhibits
documented new or worsening symptoms due to HF on presentation,
including at least one of the following: dyspnea (dyspnea with
exertion, dyspnea at rest, orthopnea, paroxysmal nocturnal
dyspnea), decreased exercise tolerance, fatigue, or other symptoms
of worsened end-organ perfusion or volume overload (must be
specified and described by the protocol); The patient has objective
evidence of new or worsening HF, consisting of at least two
physical examination findings or one physical examination finding
and at least one laboratory criterion), including: Physical
examination findings considered to be due to heart failure,
including new or worsened: Peripheral edema, increasing abdominal
distention or ascites (in the absence of primary hepatic disease),
S.sub.3 gallop, clinically significant or rapid weight gain thought
to be related to fluid retention; or Laboratory evidence of new or
worsening HF, if obtained within 24 hours of presentation,
including: increased B-type natriuretic peptide (BNP)/N-terminal
pro-BNP (NT-proBNP) concentrations consistent with decompensation
of heart failure (such as BNP >500 pg/mL or NT-proBNP >2,000
pg/mL). In patients with chronically elevated natriuretic peptides,
a significant increase should be noted above baseline, radiological
evidence of pulmonary congestion, or non-invasive or invasive
diagnostic evidence of clinically significant elevated left- or
right-sided ventricular filling pressure or low cardiac output. For
example, echocardiographic criteria could include: E/e'>15 or
D-dominant pulmonary venous inflow pattern, plethoric inferior vena
cava with minimal collapse on inspiration, or decreased left
ventricular outflow tract (LVOT) minute stroke distance (time
velocity integral [TVI]) OR right heart catheterization showing a
pulmonary capillary wedge pressure (pulmonary artery occlusion
pressure) .gtoreq.18 mmHg, central venous pressure .gtoreq.12 mmHg,
or a cardiac index <2.2 L/min/m.sup.2. The patient receives
initiation or intensification of treatment specifically for HF,
including at least one of the following: significant augmentation
in oral diuretic therapy, intravenous diuretic, inotrope, or
vasodilator therapy, or Mechanical or surgical intervention. The
mechanical or surgical intervention including mechanical
circulatory support (e.g., intra-aortic balloon pump, ventricular
assist device) and/or mechanical fluid removal (e.g.,
ultrafiltration, hemofiltration, dialysis).
New Heart Failure/Heart Failure not Requiring Hospitalization:
is defined as an event that meets all of the following: the patient
has an urgent, unscheduled office/practice or emergency department
visit for a primary diagnosis of HF, but not meeting the criteria
for a HF hospitalization; all signs and symptoms for HF
hospitalization must be met as defined in A Heart Failure
Hospitalization above; and the patient receives initiation or
intensification of treatment specifically for HF, as detailed in
the above section with the exception of oral diuretic therapy,
which was not sufficient.
Interventional Cardiology Definitions
Clinical Definitions:
Clinically-Driven Target Lesion Revascularization:
Revascularization is clinically-driven if the target lesion
diameter stenosis is >50% by quantitative coronary angiography
(QCA) and the subject has clinical or functional ischemia which
cannot be explained by another native coronary or bypass graft
lesion. Clinical or functional ischemia includes any of the
following: a history of angina pectoris, presumably related to the
target vessel; objective signs of ischemia at rest
(electrocardiographic changes) or during exercise test (or
equivalent), presumably related to the target vessel; and abnormal
results of any invasive functional diagnostic test (e.g., coronary
flow reserve [CFR] or fractional flow reserve [FFR]).
Non-Target Lesion and Non-Target Lesion Revascularization:
A lesion for which revascularization is not attempted or one in
which revascularization is performed using a non-study device,
respectively.
Non-Target Vessel and Non-Target Vessel Revascularization:
A vessel for which revascularization is not attempted or one in
which revascularization is performed using a non-study device,
respectively.
Percutaneous Coronary Intervention (PCI) Status includes: Elective:
The procedure can be performed on an outpatient basis or during a
subsequent hospitalization without significant risk of myocardial
infarction (MI) or death. For stable in-patients, the procedure is
being performed during this hospitalization for convenience and
ease of scheduling and NOT because the patient's clinical situation
demands the procedure prior to discharge. Urgent: The procedure
should be performed on an inpatient basis and prior to discharge
because of significant concerns that there is risk of myocardial
ischemia, MI, and/or death. Patients who are outpatients or in the
emergency department at the time that the cardiac catheterization
is requested would warrant hospital admission based on their
clinical presentation. Emergency: The procedure should be performed
as soon as possible because of substantial concerns that ongoing
myocardial ischemia and/or MI could lead to death. "As soon as
possible" refers to a patient who is of sufficient acuity that one
would cancel a scheduled case to perform this procedure immediately
in the next available room during business hours, or one would
activate the on-call team were this to occur during off-hours.
Salvage: The procedure is a last resort. The patient is in
cardiogenic shock when the PCI begins (i.e., the time at which the
first guide wire or intracoronary device is introduced into a
coronary artery or bypass graft for the purpose of mechanical
revascularization) or within the last ten minutes prior to the
start of the case or during the diagnostic portion of the case, the
patient has also received chest compressions or has been on
unanticipated circulatory support (e.g., intra-aortic balloon pump,
extracorporeal mechanical oxygenation, or cardiopulmonary
support).
Percutaneous Coronary Intervention (PCI):
Placement of an angioplasty guide wire, balloon, or other device
(e.g., stent, atherectomy catheter, brachytherapy delivery device,
or thrombectomy catheter) into a native coronary artery or coronary
artery bypass graft for the purpose of mechanical coronary
revascularization. In the assessment of the severity of coronary
lesions with the use of intravascular ultrasound, CFR, or FFR,
insertion of a guide wire was not considered PCI.
Peripheral Vascular Intervention Definitions:
Peripheral Vascular Intervention Definition:
Peripheral vascular intervention is a catheter-based or open
surgical procedure designed to improve peripheral arterial or
venous blood flow or otherwise modify or revise vascular conduits.
Procedures may include, but are not limited to, balloon
angioplasty, stent placement, thrombectomy, embolectomy,
atherectomy, dissection repair, aneurysm exclusion, treatment of
dialysis conduits, placement of various devices, intravascular
thrombolysis or other pharmacotherapies, and open surgical bypass
or revision. In general, the intention to perform percutaneous
peripheral vascular intervention is denoted by the insertion of a
guide wire into a peripheral artery or vein. The target vessel(s)
and the type of revascularization procedure (e.g., surgical bypass,
thrombectomy, endarterectomy, percutaneous angioplasty, stent
placement, thromboembolectomy, and thrombolysis) should be
specified and recorded. For the sake of simplicity, this definition
applies to the extracranial carotid artery and other non-cardiac
arteries and veins and excludes the intracranial vessels and
lymphatics.
Procedural Status includes: Non-Elective: Non-elective procedures
include emergent and urgent procedures. A non-elective procedure is
a procedure that is performed without delay, because there is
clinical consensus that the procedure should occur imminently.
Non-elective procedures imply a degree of instability of the
patient, urgency of the medical condition, or instability of the
threatening lesion. Emergent: A procedure that is performed
immediately because of the acute nature of the medical condition
(e.g., acute limb ischemia, acute aortic dissection), and the
increased morbidity or mortality associated with a temporal delay
in treatment. Urgent: An urgent procedure is one that is not
emergent but required to be performed on a timely basis (.ltoreq.24
hrs) (e.g., a patient who has been stabilized following initial
treatment of acute limb ischemia, and there is clinical consensus
that a definitive procedure should occur within the next 24 hours).
Elective: An elective procedure is one that is scheduled and is
performed on a patient with stable disease, or in whom there is no
urgency and/or increased morbidity or mortality associated with a
planned procedure.
Definition of Any Revascularization Procedure:
Any revascularization includes any arterial vascular intervention
done to treat ischemia or prevent major ischemic events, including
percutaneous or surgical intervention of the coronary, peripheral,
or carotid arteries. Aneurysm repairs, dissection repairs,
arterial-venous fistula or graft placement or repairs, or renal
arterial intervention for hypertension or renal dysfunction are not
included.
Definition of Cardiac Arrhythmia Requiring Hospitalization:
An arrhythmia that either results in hospitalization (.gtoreq.24
hours) during or within 24 hours of the termination of the last
episode for treatment or requires continued hospitalization for
treatment, including any one of the following: Atrial
arrhythmia--atrial fibrillation, atrial flutter, supraventricular
tachycardia that requires cardio-version, drug therapy, or is
sustained for greater than 1 minute; Ventricular
arrhythmia--Ventricular tachycardia or ventricular fibrillation
requiring cardio-version and/or intravenous antiarrhythmics; and/or
Bradyarrhythmia--High-level AV block (defined as third-degree AV
block or second-degree AV block), junctional or ventricular escape
rhythm, or severe sinus bradycardia (typically with heart rate
<30 bpm). The bradycardia must require temporary or permanent
pacing.
Definition of Cardiac Arrest (Sudden Cardiac Death):
A sudden, unexpected death due to the cessation of cardiac
mechanical activity, confirmed by the absence of a detectable
pulse, unresponsiveness, and apnea (or agonal, gasping
respirations) of presumed cardiac etiology. An arrest is presumed
to be cardiac (i.e., related to heart disease) if this is likely,
based on the available information, including hospital records and
autopsy data. The cardiac arrest is further sub-classified into
either: witnessed, occurring within 60 min from the onset of new
symptoms, in the absence of a clear cause other than
cardiovascular; or unwitnessed, within 24 hours of being observed
alive, in the absence of pre-existing other non-cardiovascular
causes of death;
Non-cardiac causes of cardiac arrest, such as drug overdose,
suicide, drowning, hypoxia, exsanguination, cerebrovascular
accident, subarachnoid hemorrhage, or trauma must not be
present.
Definition of Resuscitated Cardiac Arrest:
Resuscitated Cardiac Arrest is present when there is restoration of
both: organized electrical activity and organized mechanical
activity resulting in restoration of spontaneous circulation
(defined as the documented presence of a measurable pulse and blood
pressure at any time after initiation of resuscitative
efforts).
Criteria for the Diagnosis of Metabolic Syndrome:
The diagnosis of metabolic syndrome requires the presence of three
out of the following five specific components using the following
criteria with cut points of parameters as defined in Table 1 and
listed below, and waist circumference cut points further guided by
the Table 14. A waist circumference .gtoreq.35 inches (88 cm) for
all women, and Asian, Hispanic, or Latino men, and waist
circumference .gtoreq.40 inches (102 cm) for all other men;
Elevated TG (TG .gtoreq.150 mg/dL); Reduced HDL-C(HDL-C <40
mg/dL if male; HDL-C <50 mg/dL if female); Elevated blood
pressure (systolic .gtoreq.130 mmHg and/or diastolic 285 mmHg, or
an antihypertensive therapy with medical history of hypertension;
and Elevated fasting glucose (fasting glucose 2100 mg/dL, or on
drug therapy for elevated glucose.
TABLE-US-00015 TABLE 14 Current Recommended Waist Circumference
Thresholds for Abdominal Obesity by Organization and Population.
Waist Circumference Threshold Population Women Organization
(Reference) Men (cm) (cm) IDF (4) Europid .gtoreq.94 .gtoreq.80 WHO
(7) Caucasian .gtoreq.94 .gtoreq.80 (increased risk) .gtoreq.102
.gtoreq.88 (still higher risk) AHA/NHLBI (ATP III)* US .gtoreq.102
.gtoreq.88 Health Canada Canada .gtoreq.102 .gtoreq.88 European
Cardiovascular European .gtoreq.102 .gtoreq.88 Societies IDF Asian
.gtoreq.90 .gtoreq.80 (including Japanese) WHO Asian .gtoreq.90
.gtoreq.80 Japanese Obesity Society Japanese .gtoreq.85 .gtoreq.90
Cooperative Task Force China .gtoreq.85 .gtoreq.80 IDF Middle East,
.gtoreq.94 .gtoreq.80 Mediterranean IDF Sub-Saharan African
.gtoreq.94 .gtoreq.80 IDF Ethnic Central & .gtoreq.90
.gtoreq.80 South American IDF = International Diabetes Federation;
WHO = World Health Organization; AHA/NHLBI (ATP III) = American
Heart Association/National Heart, Lung, and Blood Institute Adult
Treatment Panel III; *Recent AHA/NHLBI guidelines for metabolic
syndrome recognize an increased risk for cardiovascular disease and
diabetes at waist-circumference thresholds of .gtoreq.94 cm in men
and .gtoreq.80 cm in women and identify these as optional cut
points for individuals or populations with increased insulin
resistance.
Statistical Analysis
In this event-driven trial, it was estimated that approximately
1612 adjudicated primary endpoint events would be necessary to
provide 90% power to detect a 15% lower risk of the primary
composite endpoint in the AMR101 group than in the placebo group.
This resulted in an estimated sample size of approximately 7990
patients to reach the number of primary endpoints. The primary
efficacy analysis was based on the time from randomization to the
first occurrence of any component of the primary composite
endpoint. If the relative risk reduction with administration of
AMR101 in the primary endpoint was significant (final two-sided
alpha level=0.0437; determined from O'Brien-Fleming boundaries
generated using the Lan-DeMets alpha-spending function after
accounting for two protocol pre-specified interim efficacy
analyses), in a hierarchical fashion, the key secondary endpoint
and other prespecified secondary endpoints were to be tested at the
same final alpha level of 0.0437. All primary efficacy analyses
followed the intent-to-treat principle. HRs and 95% CI were
generated using a Cox proportional hazard model with treatment as
covariate, and stratified by cardiovascular risk category,
geographic region, and use of ezetimibe. Log-rank P values were
reported from a Kaplan-Meier analysis, stratified by the three
randomization factors, to evaluate the timing of events in the two
treatment groups.
Results
Subject Disposition:
The subject disposition by treatment group is depicted in FIG. 2. A
total of 19,212 patients were screened of whom 8,179 (43%) were
randomized. At the time of database lock, vital status was
available in 99.8%; 152 (1.9%) patients did not complete final
study visits and 578 (7.1%) patients withdrew consent. Demographic
and Baseline Disease Characteristics: Among the patients who
underwent randomization, 70.7% were enrolled on the basis of
secondary prevention (i.e., patients had established cardiovascular
disease) and 29.3% for primary prevention (i.e., patients had
diabetes mellitus and at least one additional risk factor). The
median age was 64 years, 28.8% were female, and 38.5% were from the
United States. At baseline, the median LDL-cholesterol was 75.0
mg/dL, HDL-cholesterol was 40.0 mg/dL, and triglycerides were 216.0
mg/dL. The baseline characteristics of the patients are provided
below in Table 16.
TABLE-US-00016 TABLE 16 Demographic and Randomization
Stratification Information of the ITT Population Icosapent ethyl
Placebo (N = 4089) (N = 4090) Age (years), Median 64.0 (57.0-69.0)
64.0 (57.0-69.0) (Q1-Q3) Female, (n %) 1162 (28.4%) 1195 (29.2%)
Non-White, (n %) 398 (9.7%) 401 (9.8%) Age .gtoreq.65 years, n (%)
1857 (45.4%) 1906 (46.6%) Male, n (%) 2927 (71.6%) 2895 (70.8%)
White, n (%).sup.[1] 3691 (90.3%) 3688 (90.2%) BMI (kg/m.sup.2),
Median 30.8 (27.8-34.5) 30.8 (27.9-34.7) (Q1-Q3) BMI .gtoreq.30
(kg/M.sup.2), n (%) 2331 (57.0%) 2362 (57.8%) Geographic Region, n
(%) Westernized.sup.[2] 2906 (71.1%) 2905 (71.0%) Eastern
Europe.sup.[3] 1053 (25.8%) 1053 (25.7%) Asia Pacific.sup.[4] 130
(3.2%) 132 (3.2%) CV Risk Category, n (%) Secondary Prevention 2892
(70.7%) 2893 (70.7%) Primary Prevention 1197 (29.3%) 1197 (29.3%)
Ezetimibe Use, n (%) 262 (6.4%) 262 (6.4%) Statin Intensity, n (%)
Low 254 (6.2%) 267 (6.5%) Moderate 2533 (61.9%) 2575 (63.0%) High
1290 (31.5%) 1226 (30.0%) Missing 12 (0.3%) 22 (0.5%) Diabetes, n
(%) Type I Diabetes 27 (0.7%) 30 (0.7%) Type II Diabetes 2367
(57.9%) 2363 (57.8%) No Diabetes at Baseline 1695 (41.5%) 1694
(41.4%) Data Missing 0 3 (0.1%) hsCRP (mg/L), Median 2.2 (1.1-4.5)
2.1 (1.1-4.5) (Q1-Q3) Triglycerides (mg/dL), 216.5 (176.5-272.0)
216.0 (175.5-274.0) Median (Q1-Q3) HDL-C (mg/dL), Median 40.0
(34.5-46.0) 40.0 (35.0-46.0) (Q1-Q3) LDL-C (mg/dL), Median 74.0
(61.5-88.0) 76.0 (63.0-89.0) (Q1-Q3) Triglycerides Category <150
mg/dL 412 (10.1%) 429 (10.5%) 150 to <200 mg/dL 1193 (29.2%)
1191 (29.1%) .gtoreq.200 mg/dL 2481 (60.7%) 2469 (60.4%)
Triglycerides 823 (20.1%) 794 (19.4%) .gtoreq.200 mg/dL and HDL-C
.ltoreq.35 mg/dL EPA (.mu.g/mL), Median 26.1 (17.1-40.1) 26.1
(17.1-39.9) (Q1-Q3) In general, the baseline value is defined as
the last non-missing measurement obtained prior to the
randomization. The baseline LDL-C value obtained via Preparative
Ultracentrifugation was used, unless this value was missing. If the
LDL-C Preparative Ultracentrifugation value was missing, then
another LDL-C value was be used, with prioritization of values
obtained from LDL-C Direct measurements, followed by LDL-C derived
by the Friedewald calculation (only for patients with TG <400
mg/dL), and finally LDL-C derived using the calculation published
by Johns Hopkins University investigators.22 At Visit 1 and Visit
1.1 Direct LDL-C was used if at the same visit TG >400 mg/dL At
alll remaining visits LDL-C was measured by Direct LDL-C or by
Preparative Ultracentrifugation if at the same visit TG >400
mg/dL. For all other lipid and lipoprotein marker parameters,
wherever possible, baseline was derived as the arithmetic mean of
the Visit 2 (Day 0) value and the preceding Visit 1 (or Visit 1.1)
value. If only one of these values was available, the single
available value was used as baseline. The only significant baseline
between group difference with p < 0.05 was LDL-C (p = 0.03).
.sup.[1]Race as reported by the investigators. .sup.[2]Westernized
region includes Australia; Canada, Netherlands, New Zealand, United
States, and South Africa. .sup.[3]Eastern European region includes
Poland; Romania, Russian Federation, and Ukraine. .sup.[4]Asia
Pacific region includes India.
The median trial follow-up duration was 4.9 years with a maximum of
6.2 years. The median change in triglycerides from baseline to one
year was -18.3% (-39.0 mg/dL) in the AMR101 group and +2.2% (4.5
mg/dL) in the placebo group; the median reduction from baseline (as
estimated with the use of the Hodges-Lehmann approach) was 19.7%
greater in the AMR101 group than in the placebo group (a 44.5 mg/dL
[0.50 mmol/L] greater reduction; P<0.001). The median change in
LDL cholesterol level from baseline was an increase of 3.1% (2.0
mg/dL [0.05 mmol/L]) in the AMR101 group and an increase of 10.2%
(7.0 mg/dL [0.18 mmol/L]) in the placebo group--a 6.6% (5.0 mg/dL
[0.13 mmol/L]) lower increase with AMR101 than with placebo
(P<0.001).
Analyses of Primary Composite Endpoint:
There were a total of 1606 adjudicated primary endpoint first
events. FIG. 3A shows the Kaplan-Meier event curves for the primary
efficacy endpoint of time to first occurrence of cardiovascular
death, nonfatal myocardial infarction, nonfatal stroke, coronary
revascularization, or unstable angina in the AMR101 and placebo
groups with the inset showing the data on an expanded y axis. All
patients were included in the analysis and patients experiencing
more than one type of endpoint event were counted for their first
occurrence in each event type. The primary endpoint as shown in
FIG. 3A occurred in 17.2% of AMR101 patients versus in 22.0% of
placebo patients (HR, 0.75; 95% CI, 0.68-0.83; P<0.001) for an
absolute risk reduction (AAR) of 4.8% (95% CI, 3.1-6.5%) and number
needed to treat (NNT) of 21 (95% CI, 15-33) over median follow up
4.9 years. Similarly, FIG. 3B shows the Kaplan-Meier estimates of
the cumulative incidence of the primary composition endpoints over
time. Significantly, FIG. 3B indicates a 25% relative risk
reduction for the primary composite endpoint over the course of 5
years.
FIG. 4 lists the individual components of the primary endpoint
analyzed as time to first event of each individual endpoint. Shown
first in FIG. 4 is the HR and 95% CI for the primary composite
endpoint event (time to first occurrence of either cardiovascular
death, nonfatal myocardial infarction, nonfatal stroke, coronary
revascularization, or unstable angina). Shown separately beneath
FIG. 4 are HRs and 95% CIs for time to first occurrence of each
type of individual primary endpoint component event, irrespective
of whether contributing to the primary composite endpoint event or
not.
Analyses of Key Secondary Endpoints:
FIG. 5A shows the Kaplan-Meier event curves for the key secondary
efficacy endpoint of time to first occurrence of cardiovascular
death, nonfatal myocardial infarction, or nonfatal stroke in the
AMR101 and placebo groups with the inset showing the data on an
expanded y axis. All patients were included in the analysis and
patients experiencing more than one type of endpoint event were
counted for their first occurrence in each event type. The key
secondary efficacy endpoint as shown in FIG. 5A occurred in 11.2%
of AMR101 patients versus 14.8% of placebo patients (HR, 0.74, 95%
CI 0.65-0.83, P<0.001) for an absolute risk reduction of 3.6%
(95% CI, 2.1-5.0%) and a number needed to treat of 28 (95% CI,
20-47) over median follow up 4.9 years. Similarly, FIG. 5B shows
the Kaplan-Meier estimates of the cumulative incidence of the key
secondary composition endpoints over time. Significantly, FIG. 5B
indicates a 26% relative risk reduction for the key secondary
composite endpoint over the course of 5 years.
Analysis of Prespecified Subgroups
The primary efficacy outcomes in select prespecified subgroups are
shown in FIGS. 6 and 7 with corresponding HRs and 95% CIs for the
primary efficacy endpoint of time to first occurrence of
cardiovascular death, nonfatal myocardial infarction, nonfatal
stroke, coronary revascularization, or unstable angina from select
prespecified subgroups in the AMR101 and placebo groups. The key
secondary efficacy outcomes in select prespecified subgroups are
shown in FIGS. 8 and 9 with corresponding HRs and 95% CIs for the
key secondary efficacy endpoint of time to first occurrence of
cardiovascular death, nonfatal myocardial infarction, nonfatal
stroke, coronary revascularization, or unstable angina from select
prespecified subgroups in the AMR101 and placebo groups.
Significantly, FIGS. 6-9 indicate that a subject's baseline
triglyceride levels (e.g., .gtoreq.150 vs. <150 mg/dL or
.gtoreq.200 or <200 mg/dL) had no influence on the primary or
key secondary efficacy endpoints.
This conclusion is further substantiated by the combination of
FIGS. 10A and 10B which show that achievement of on-treatment
triglyceride levels above or below 150 mg/dL at one year did not
influence the efficacy of AMR101 versus placebo. In particular,
FIGS. 10A and 10B show the primary and key secondary endpoints by
achieved triglyceride level (e.g., above or below 150 mg/dL) at 1
year (e.g., patients with a triglyceride level above or below 150
mg/dL after 1 year of having received the AMR101). FIG. 10A are the
Kaplan-Meier curves for the primary endpoint of time to first
occurrence of cardiovascular death, nonfatal myocardial infarction,
nonfatal stroke, coronary revascularization, or unstable angina in
the AMR101 treatment group for patients with achieved
triglycerides, and the placebo group at year 1. Conversely, FIG.
10B are the Kaplan-Meier event curves for the key secondary
endpoint of time to first occurrence of cardiovascular death,
nonfatal myocardial infarction, or nonfatal stroke in the AMR101
treatment group for patients with achieved triglycerides, and the
placebo group at year 1. Importantly, FIGS. 10A and 10B indicate
that regardless of the subject's triglyceride levels at year 1, the
subject experienced a statistically significant reduction in time
to first occurrence of cardiovascular death, nonfatal myocardial
infarction, nonfatal stroke, coronary revascularization, or
unstable angina. The attainment of triglyceride levels of 150 mg/dL
or higher or below 150 mg/dL at 1 year after randomization also had
no influence on the efficacy of AMR101 as compared with placebo
with respect to the primary or key secondary efficacy endpoint. In
a post hoc analysis, no substantial difference in the benefit of
AMR101 as compared with placebo was observed with respect to the
primary endpoint according to whether the patients who received
placebo had an increase in LDL cholesterol levels at 1 year or had
no change or a decrease in LDL cholesterol levels.
FIG. 11 depicts the prespecified hierarchical testing of the
endpoints; except for the last hierarchical secondary endpoint of
death from any cause (also referred to as total mortality), all
other individual and composite ischemic endpoints were
significantly reduced by AMRI01, including cardiovascular death
(4.3% versus 5.2%; HR, 0.80; 95% CI, 0.66-0.98; P=0.03). Total
mortality was 6.7% versus 7.6% (HR, 0.87; 95% CI, 0.74-1.02;
P=0.09) in the AMR101 and placebo groups, respectively. For each of
the prespecified endpoints in FIG. 11, icosapent ethyl 4 g per day
provide a RRR of 25% for the primary composite endpoint, 26% for
the secondary composite endpoint, 25% for the composite of
cardiovascular death or nonfatal myocardial infarction, 31% for
fatal or nonfatal myocardial infarction, 35% for urgent or emergent
revascularization, 20% for cardiovascular death, 32% for
hospitalization for unstable angina, 28% for fatal or nonfatal
stroke, 23% reduction in the composite of total mortality, nonfatal
myocardial infarction, or nonfatal stroke, and lastly, a 13%
reduction in total mortality.
Results for selected tertiary outcomes are shown in Table 17. A
tertiary endpoint, adjudicated sudden cardiac death was 2.1% versus
1.5% (HR, 0.69; 95% CI, 050-0.96).
TABLE-US-00017 TABLE 17 Selected Prespecified Adjudicated Tertiary
Endpoints Icosapent Ethyl Placebo Tertiary Endpoint n/N (%) n/N (%)
HR (95% CI) Primary Endpoint in 433/2394 (18.1%) 536/2393 (22.4%)
0.77 (0.68, 0.87) Patients with Diabetes at Baseline New Heart
Failure 169/4089 (4.1%) 176/4090 (4.3%) 0.95 (0.77, 1.17) New Heart
Failure 141/4089 (3.4%) 144/4090 (3.5%) 0.97 (0.77, 1.22) Requiring
Hospitalization Transient Ischemic Attack 64/4089 (1.6%) 48/4090
(1.2%) 1.32 (0.91, 1.92) Amputation for PVD 22/4089 (0.5%) 21/4090
(0.5%) 1.04 (0.57, 1.89) Carotid Revascularization 31/4089 (0.8%)
26/4090 (0.6%) 1.18 (0.70, 1.98) Coronary Revascularization
376/4089 (9.2%) 544/4090 (13.3%) 0.66 (0.58, 0.76) Emergent
Revascularization 41/4089 (1.0%) 65/4090 (1.6%) 0.62 (0.42, 0.92)
Urgent Revascularization 181/4089 (4.4%) 268/4090 (6.6%) 0.66
(0.54, 0.79) Elective Revascularization 194/4089 (4.7%) 278/4090
(6.8%) 0.68 (0.57, 0.82) Salvage Revascularization 0/4089 (0.0%)
2/4090 (0.0%) 0.00 (0.00, --) Cardiac Arrhythmias 188/4089 (4.6%)
154/4090 (3.8%) 1.21 (0.97, 1.49) Requiring Hospitalization of
.gtoreq.24 Hours Cardiac Arrest 22/4089 (0.5%) 42/4090 (1.0%) 0.52
(0.31, 0.86) Sudden Cardiac Death 61/4089 (1.5%) 87/4090 (2.1%)
0.69 (0.50, 0.96) Ischemic Stroke 80/4089 (2.0%) 122/4090 (3.0%)
0.64 (0.49, 0.85) Hemorrhagic Stroke 13/4089 (0.3%) 10/4090 (0.2%)
1.28 (0.56, 2.93) New Onset of Diabetes.sup.[1] 65/1695 (3.8%)
63/1697 (3.7%) 1.04 (0.73, 1.47) .sup.[1]Patents with diabetes at
baseline are excluded from this endpoint analysis.
Analysis of Additional Biomarker from Baseline:
The effects on additional biomarkers to year 1 are shown in Table
18.
TABLE-US-00018 TABLE 18 Effect on Biomarkers from Baseline to Year
1 Median Between Group Difference at Year 1 Icosapent Ethyl Placebo
Absolute % (N = 4089) (N = 4090) Change Change % Median Median from
from Change Biomarker Baseline Year 1 Baseline Year 1 Baseline
Baseline P-value Triglycerides (mg/dL) 216.5 175.0 216.0 221.0
-44.5 -19.7 <0.0001 Non-HDL-C (mg/dL) 118.0 113.0 118.5 130.0
-15.5 -13.1 <0.0001 LDL-C (mg/dL) 74.5 77.0 76.0 84.0 -5.0 -6.6
<0.0001 HDL-C (mg/dL) 40.0 39.0 40.0 42.0 -2.5 -6.3 <0.0001
Apo B (mg/dL) 82.0 80.0 83.0 89.0 -8.0 -9.7 <0.0001 hsCRP (mg/L)
2.2 1.8 2.1 2.8 -0.9 -39.9 <0.0001 EPA (.mu.g/mL) 26.1 144.0
26.1 23.3 114.9 358.8 <0.0001
The effects on lipid, lipoprotein, and inflammatory marker overtime
for the ITT population are shown in Table 19.
TABLE-US-00019 TABLE 19 Lipid, Lipoprotein, and Inflammatory Marker
Data Over Time for the ITT Population Icosapent Ethyl (N = 4089)
Placebo (N = 4090) Median Median Absolute Median % Absolute Median
Change Change Median % Median Change Observed from from Change
Observed from Biomarker Visit Value Baseline Baseline
P-value.sup.[1] Value Baseline Triglycerides Baseline 216.5 216.0
(mg/dL) Month 4 177.0 -37.5 -18.6 <0.001 221.0 5.5 Year 1 175.0
-39.0 -18.3 <0.001 221.0 4.5 Year 2 173.0 -38.5 -18.9 <0.001
220.0 4.3 Year 3 167.0 -44.0 -21.7 <0.001 212.0 1.0 Year 4 163.0
-42.5 -21.7 <0.001 200.0 -7.0 Year 5 158.0 -38.0 -20.0 <0.001
193.0 -3.0 Last Visit 170.0 -45.0 -21.6 <0.001 202.0 -13.0
Non-HDL-C Baseline 118.0 118.5 (mg/dL) Month 4 113.0 -4.5 -4.0
<0.001 128.0 9.5 Year 1 113.0 -4.0 -3.6 <0.001 130.0 12.0
Year 2 113.0 -3.5 -3.1 0.002 129.0 11.5 Year 3 112.0 -4.8 -4.2
<0.001 128.0 10.5 Year 4 110.5 -5.0 -4.2 <0.001 126.0 9.5
Year 5 109.0 -5.0 -4.4 0.004 123.0 7.0 Last Visit 112.0 -5.0 -4.4
<0.001 124.0 6.0 LDL-C derived Baseline 74.0 76.0
(mg/dL).sup.[4] Year 1 77.0 2.0 3.1 <0.001 84.0 7.0 Last Visit
77.0 2.0 3.1 <0.001 84.0 7.0 LDL-C Hopkins Baseline 85.8 86.7
(mg/dL) Month 4 83.6 -1.6 -2.0 0.01 93.7 7.3 Year 1 85.3 -1.1 -1.2
0.06 95.8 9.3 Year 2 85.5 -0.1 -0.2 <0.001 96.1 9.5 Year 3 84.6
-1.0 -1.2 0.01 95.7 9.0 Year 4 83.6 -0.5 -0.6 0.07 94.7 8.8 Year 5
82.2 -0.8 -0.7 0.23 91.6 6.2 Last Visit 84.0 -1.0 -1.2 0.14 92.1
5.7 HDL-C Baseline 40.0 40.0 (mg/dL) Month 4 39.0 -1.0 -2.8
<0.001 42.0 2.0 Year 1 39.0 -1.0 -2.6 <0.001 42.0 1.5 Year 2
40.0 0.0 0.0 0.21 42.0 1.5 Year 3 40.0 0.0 0.0 0.006 42.0 1.5 Year
4 40.5 0.5 1.0 <0.001 43.0 2.0 Year 5 41.0 0.0 0.0 0.02 43.0 1.5
Last Visit 41.0 1.0 2.5 <0.001 42.0 2.0 Apo B Baseline 82.0 83.0
(mg/dL) Year 2 80.0 -2.0 -2.5 0.05 89.0 6.0 Last Visit 80.0 -2.0
-2.5 0.06 86.0 4.0 hsCRP Baseline 2.2 2.1 (mg/L) Year 2 1.8 -0.2
-13.9 0.04 2.8 0.5 Last Visit 1.8 -0.2 -12.6 0.75 2.8 0.4 Log hsCRP
Baseline 0.8 0.8 (mg/L) Year 2 0.6 -0.1 -21.8 <.0001 1.0 0.3
Last Visit 0.6 -0.1 -23.1 <.0001 1.0 0.3 EPA Baseline 26.1 26.1
(.mu.g/mL).sup.[5] Year 1 144.0 112.6 393.5 <0.001 23.3 -2.9
Between Group Difference Placebo (N = 4090) Median Median %
Absolute Median % Change Median % Change Change Median % from
Change from from Change Biomarker Visit Baseline P-value.sup.[1]
Baseline.sup.[2] Baseline.sup.[2- ] P value.sup.[3] Triglycerides
Baseline (mg/dL) Month 4 2.7 <0.001 -45.5 -20.1 <0.001 Year 1
2.2 <0.001 -44.5 -19.7 <0.001 Year 2 2.1 <0.001 -43.8
-19.7 <0.001 Year 3 0.4 <0.001 -45.5 -20.3 <0.001 Year 4
-3.7 >0.99 -38.0 -17.4 <0.001 Year 5 -1.5 0.23 -33.5 -16.7
<0.001 Last Visit -6.5 <0.001 -32.0 -14.1 <0.001 Non-HDL-C
Baseline (mg/dL) Month 4 8.2 <0.001 -14.3 -12.2 <0.001 Year 1
10.4 <0.001 -15.5 -13.1 <0.001 Year 2 9.8 <0.001 -14.5
-12.5 <0.001 Year 3 9.2 <0.001 -14.5 -12.4 <0.001 Year 4
8.1 <0.001 -14.0 -12.0 <0.001 Year 5 6.1 <0.001 -11.0 -9.9
<0.001 Last Visit 5.1 <0.001 -10.0 -8.6 <0.001 LDL-C
derived Baseline (mg/dL).sup.[4] Year 1 10.2 <0.001 -5.0 -6.6
<0.001 Last Visit 10.2 <0.001 -5.0 -6.6 <0.001 LDL-C
Hopkins Baseline (mg/dL) Month 4 8.7 <0.001 -8.7 -10.3 <0.001
Year 1 10.9 <0.001 -9.6 -11.4 <0.001 Year 2 11.4 <0.001
-9.4 -11.1 <0.001 Year 3 10.5 <0.001 -8.7 -10.4 <0.001
Year 4 10.1 <0.001 -8.9 -10.6 <0.001 Year 5 6.9 <0.001
-6.6 -8.0 <0.001 Last Visit 6.5 <0.001 -6.2 -7.4 <0.001
HDL-C Baseline (mg/dL) Month 4 4.7 <0.001 -3.0 -7.2 <0.001
Year 1 3.8 <0.001 -2.5 -6.3 <0.001 Year 2 4.2 <0.001 -2.0
-4.6 <0.001 Year 3 4.0 <0.001 -1.5 -3.8 <0.001 Year 4 4.8
<0.001 -1.5 -3.9 <0.001 Year 5 3.0 <0.001 -1.5 -3.0
<0.001 Last Visit 5.7 <0.001 -1.0 -3.0 <0.001 Apo B
Baseline (mg/dL) Year 2 7.8 <0.001 -8.0 -9.7 <0.001 Last
Visit 4.5 <0.001 -5.0 -6.7 <0.001 hsCRP Baseline (mg/L) Year
2 32.3 <0.001 -0.9 -39.9 <0.001 Last Visit 29.9 <0.001
-0.8 -37.6 <0.001 Log hsCRP Baseline (mg/L) Year 2 0.0 0.9203
-0.4 -22.5 <.0001 Last Visit -4.0 0.0481 -0.4 -21.2 <.0001
EPA Baseline (.mu.g/mL).sup.[5] Year 1 -12.8 <0.001 114.9 358.8
<0.001
Safety Results
The results from this study showed no new or unexpected important
adverse effects were observed in the safety population for this
study as shown below in Tables 20 and 21. These conclusions are
consistent with the independent DMC review conclusions and with
quarterly safety review conclusions.
TABLE-US-00020 TABLE 20 Overview of Treatment-Emergent Adverse
Events of the Safety Population AMR101 Placebo (N = 4089) (N =
4090) p-value.sup.[1] Subjects with at Least One TEAE.sup.[2], n(%)
3343 (81.8%) 3326 (81.3%) 0.63 Serious TEAE 1252 (30.6%) 1254
(30.7%) 0.98 TEAE Leading to Withdrawal of Study Drug.sup.[3] 321
(7.9%) 335 (8.2%) 0.60 Serious TEAE Leading to Withdrawal of Study
88 (2.2%) 88 (2.2%) 1.00 Drug.sup.[3] Serious TEAE Leading to
Death.sup.[4] 94 (2.3%) 102 (2.5%) 0.61 Note: A treatment-emergent
adverse event (TEAE) is defined as an event that first occurs or
worsens in severity on or after the date of dispensing study drug
and within 30 days after the completion or withdrawal from study.
Percentages are based on the number of patients randomized to each
treatment group in the Safety population (N). Events that were
positively adjudicated as clinical endpoints are not included.
.sup.[1]P-value from Fisher's Exact test. .sup.[2]All adverse
events are coded using the Medical Dictionary for Regulatory
Activities (MedDRA Version 20.1). .sup.[3]Withdrawal of study drug
excludes patents who were off drug in study (ODIS) for 30 days or
more, and restarted study drug. .sup.[4]The most common serious
TEAEs leading to death by system organ class were neoplasms (1.1%);
infections and infestations (0.4%); respiratory, thoracic, and
mediastinal disorders (0.2%): cardiac disorders (0.2%); and
vascular disorders (0.1%). No serious TEAEs leading to death by
system organ class were statistically significant across treatment
groups except for cardiac disorders: which occurred in 3 (0.1%) of
VASCEPA .RTM. patients and 15 (0.4%) of placebo patents (p =
0.008).
TABLE-US-00021 TABLE 21 Serious Bleeding Treatment-Emergent Adverse
Events by Preferred term. Icosapent Ethyl Placebo Preferred Term (N
= 4089) (N = 4090) p-value.sup.[1] Bleeding related disorders 111
(2.7%) 85 (2.1%) 0.06 Gastrointestinal bleeding 62 (1.5%) 47 (1.1%)
0.15 Central nervous system 14 (0.3%) 10 (0.2%) 0.42 bleeding Other
bleeding 41 (1.0%) 30 (0.7%) 0.19 Note: A treatment-emergent
adverse event (TEAE) is defined as an event that first occurs or
worsens in severity on or after the date of dispensing study drug
and within 30 days after the completion or withdrawal from study.
Percentages are based on the number of subjects randomized to each
treatment group in the Safety population (N). Events that were
positively adjudicated as clinical endpoints are not included. All
adverse events are coded using the Medical Dictionary for
Regulatory Activities (MedDRA Version 20.1). .sup.[1]Fishers Exact
test.
Adverse events occurring in .gtoreq.5% are reported in Table 22.
Compared with placebo, AMR101 was associated with a significantly
higher rate of atrial fibrillation (5.3% versus 3.9%), and
peripheral edema (6.5% vs 5%), but a lower rate of diarrhea (9% vs
11.1%), anemia (4.7% vs 5.8%), and gastrointestinal adverse events
(33.0% to 35.1%). There was no significant difference in the
prespecified adjudicated tertiary endpoint of heart failure (4.1%
vs 4.3%). The prespecified adjudicated tertiary endpoint of atrial
fibrillation or flutter requiring hospitalization was more common
with the AMR101 group than the placebo group (3.1% vs 2.1%;
P=0.004).
TABLE-US-00022 TABLE 22 Number (%) Patients with Most Frequent
Treatment-Emergent Adverse Events (.gtoreq.5%) in Either Treatment
Group By Preferred Term for the Safety Population Icosapent Ethyl
Placebo Preferred Term (N = 4089) (N = 4090) P-value.sup.[1]
Diarrhea 367 (9.0%) 453 (11.1%) 0.002 Back pain 335 (8.2%) 309
(7.6%) 0.29 Hypertension 320 (7.8%) 344 (8.4%) 0.35 Nasopharyngitis
314 (7.7%) 300 (7.3%) 0.56 Arthralgia 313 (7.7%) 310 (7.6%) 0.90
Upper respiratory tract 312 (7.6%) 320 (7.8%) 0.77 infection
Bronchitis 306 (7.5%) 300 (7.3%) 0.80 Chest pain 273 (6.7%) 290
(7.1%) 0.48 Peripheral edema 267 (6.5%) 203 (5.0%) 0.002 Pneumonia
263 (6.4%) 277 (6.8%) 0.56 Influenza 263 (6.4%) 271 (6.6%) 0.75
Dyspnea 254 (6.2%) 240 (5.9%) 0.52 Urinary tract infection 253
(6.2%) 261 (6.4%) 0.75 Cough 241 (5.9%) 241 (5.9%) 1.00
Osteoarthritis 241 (5.9%) 218 (5.3%) 0.27 Dizziness 235 (5.7%) 246
(6.0%) 0.64 Pain in extremity 235 (5.7%) 241 (5.9%) 0.81 Cataract
233 (5.7%) 208 (5.1%) 0.22 Fatigue 228 (5.6%) 196 (4.8%) 0.11
Constipation 221 (5.4%) 149 (3.6%) <0.001 Atrial fibrillation
215 (5.3%) 159 (3.9%) 0.003 Angina pectoris 200 (4.9%) 205 (5.0%)
0.84 Anemia 191 (4.7%) 236 (5.8%) 0.03 Note: A treatment-emergent
adverse event (TEAE) is defined as an event that first occurs or
worsens in severity on or after the date of dispensing study drug
and within 30 days after the completion or withdrawal from study.
Percentages are based on the number of patients randomized to each
treatment group in the Safety population (N). Events that were
positively adjudicated as clinical endpoints are not included. All
adverse events are coded using the Medical Dictionary for
Regulatory Activities (MedDRA Version 20.1). .sup.[1]P-value from
Fishers Exact test.
Serious treatment-emergent events occurring in 22% are reported in
Table 23.
TABLE-US-00023 TABLE 23 Number (%) Patients with Serious
Treatment-Emergent Adverse Events (.gtoreq.2%) in Either Treatment
Group) By Preferred Term Icosapent Ethyl Placebo Preferred Term (N
= 4089) (N = 4090) p-value.sup.[1] Pneumonia 105 (2.6%) 118 (2.9%)
0.42 Note: A treatment-emergent adverse event (TEAE) is defined as
an event that first occurs or worsens in severity on or after the
date of dispensing study drug and within 30 days after the
completion or withdrawal from study. Percentages are based on the
number of subjects randomized to each treatment group in the Safety
population (N). Events that were positively adjudicated as clinical
endpoints are not included. All adverse events are coded using the
Medical Dictionary for Regulatory Activities (MedDRA Version 20.1).
.sup.[1]Fishers Exact test.
Adjudicated events from hospitalization for arterial fibrillation
or atrial flutter are reported in Table 24.
TABLE-US-00024 TABLE 24 Number (%) Patients with Serious
Treatment-Emergent Adverse Events (.gtoreq.2%) in Either Treatment
Group) By Preferred Term Icosapent Ethyl Placebo Preferred Term (N
= 4089) (N = 4090) p-value.sup.[1] Positively Adjudicated Atrial
127 (3.1%) 84 (2.1%) 0.0037 Fibrillation/Flutter.sup.[1] Note: A
treatment-emergent adverse event (TEAE) is defined as an event that
first occurs or worsens in severity on or after the date of
dispensing study drug and within 30 days after the completion or
withdrawal from study. Percentages are based on the number of
subjects randomized to each treatment group in the Safety
population (N). Events that were positively adjudicated as clinical
endpoints are not included. All adverse events are coded using the
Medical Dictionary for Regulatory Activities (MedDRA Version 20.1).
.sup.[1]Fishers Exact test.
Tolerability of gastrointestinal TEAS in either treatment group are
reported are reported in Table 25.
TABLE-US-00025 TABLE 25 Tolerability of gastrointestinal TEAS
Primary System Organ Icosapent Ethyl Placebo Class Preferred Term
(N = 4089) (N = 4090) P-value.sup.[1] Gastrointestinal disorders
1350 (33.0%) 1437 (35.1%) 0.04 Diarrhea 367 (9.0%) 453 (11.1%)
0.002 Constipation 221 (5.4%) 149 (3.6%) <0.001 Nausea 190
(4.6%) 197 (4.8%) 0.75 Gastroesophageal Reflux 124 (3.0%) 118
(2.9%) 0.70 Disease Note: A treatment-emergent adverse event (TEAE)
is defined as an event that first occurs or worsens in severity on
or after the date of dispensing study drug and within 30 days after
the completion or withdrawal from study. Percentages are based on
the number of patients randomized to each treatment group in the
Safety population (N). Events that were positively adjudicated as
clinical endpoints are not included. All adverse events are coded
using the Medical Dictionary for Regulatory Activities (MedDRA
Version 20.1). .sup.[1]P value from Fisher's Exact test.
When grouping treatment-emergent serious adverse events for
bleeding, the rate was 2.7% in the AMR101 group versus 2.1% in the
placebo group (P=0.06), although there were no fatal bleeding
events in either group, and no significant increases in adjudicated
hemorrhagic stroke (0.3% vs 0.2%; P=0.55), serious central nervous
system bleeding (0.3% versus 0.2%; P=0.42), or gastrointestinal
bleeding (1.5% versus 1.1%; P=0.15). Table 26 enumerates the
serious bleeding treatment-emergent adverse events by preferred
term.
TABLE-US-00026 TABLE 26 Assessment of Serious Bleeding
Treatment-Emergent Adverse Events by Category and by Preferred
Term. Icosapent Ethyl Placebo (N = 4089) (N = 4090) P Value.sup.[1]
Patients with Bleeding-Related Disorders.sup.[2] 111 (2.7%) 85
(2.1%) 0.06 By Category Gastrointestinal Bleeding.sup.[3] 62 (1.5%)
47 (1.1%) 0.15 Central Nervous System Bleeding.sup.[4] 14 (0.3%) 10
(0.2%) 0.42 Other Bleeding.sup.[5] 41 (1.0%) 30 (0.7%) 0.19 By
Preferred Term Gastrointestinal Hemorrhage 26 (0.6%) 20 (0.5%) 0.38
Rectal Hemorrhage 10 (0.2%) 6 (0.1%) 0.33 Subdural Hematoma 9
(0.2%) 5 (0.1%) 0.30 Hematuria 8 (0.2%) 4 (0.1%) 0.27 Epistaxis 7
(0.2%) 4 (0.1%) 0.39 Lower Gastrointestinal Hemorrhage 5 (0.1%) 4
(0.1%) 0.75 Post Procedural Hemorrhage 5 (0.1%) 3 (0.1%) 0.51
Hemorrhagic Anemia 4 (0.1%) 1 (0.0%) 0.22 Gastric Ulcer Hemorrhage
3 (0.1%) 1 (0.0%) 0.37 Hematemesis 3 (0.1%) 0 (0.0%) 0.12
Hemorrhoidal Hemorrhage 3 (0.1%) 1 (0.0%) 0.37 Melaena 3 (0.1%) 4
(0.1%) >0.99 Upper Gastrointestinal Hemorrhage 3 (0.1%) 3 (0.1%)
>0.99 Diverticulum Intestinal Hemorrhagic 3 (0.1%) 3 (0.1%)
>0.99 Shock Hemorrhagic 2 (0.0%) 0 (0.0%) 0.25 Cystitis
Hemorrhagic 2 (0.0%) 0 (0.0%) 0.25 Subarachnoid Hemorrhage 2 (0.0%)
1 (0.0%) 0.62 Subdural Hemorrhage 2 (0.0%) 1 (0.0%) 0.62 Traumatic
Hematoma 2 (0.0%) 1 (0.0%) 0.62 Duodenal Ulcer Hemorrhage 2 (0.0%)
0 (0.0%) 0.25 Aortic Aneurysm Rupture 1 (0.0%) 1 (0.0%) >0.99
Ecchymosis 1 (0.0%) 0 (0.0%) 0.50 Extravasation Blood 1 (0.0%) 0
(0.0%) 0.50 Gastric Hemorrhage 1 (0.0%) 3 (0.1%) 0.62
Gastrointestinal Angiodysplasia Hemorrhagic 1 (0.0%) 0 (0.0%) 0.50
Genital Hemorrhage 1 (0.0%) 0 (0.0%) 0.50 Hematochezia 1 (0.0%) 2
(0.0%) >0.99 Hematoma 1 (0.0%) 1 (0.0%) >0.99 Hemoptysis 1
(0.0%) 0 (0.0%) 0.50 Hemorrhagic Transformation Stroke 1 (0.0%) 0
(0.0%) 0.50 Hemothorax 1 (0.0%) 1 (0.0%) >0.99 Intra-Abdominal
Hemorrhage 1 (0.0%) 0 (0.0%) 0.50 Large Intestinal Hemorrhage 1
(0.0%) 1 (0.0%) >0.99 Mallory-Weiss Syndrome 1 (0.0%) 0 (0.0%)
0.50 Menorrhagia 1 (0.0%) 0 (0.0%) 0.50 Pancreatitis Hemorrhagic 1
(0.0%) 0 (0.0%) 0.50 Peptic Ulcer Hemorrhage 1 (0.0%) 0 (0.0%) 0.50
Post Procedural Hematoma 1 (0.0%) 1 (0.0%) >0.99 Retinal
Hemorrhage 1 (0.0%) 1 (0.0%) >0.99 Retroperitoneal Hemorrhage 1
(0.0%) 0 (0.0%) 0.50 Ulcer Hemorrhage 1 (0.0%) 0 (0.0%) 0.50
Urinary Bladder Hemorrhage 1 (0.0%) 1 (0.0%) >0.99 Hemarthrosis
0 (0.0%) 1 (0.0%) >0.99 Brain Contusion 0 (0.0%) 2 (0.0%) 0.50
Intracranial Hemorrhage 0 (0.0%) 1 (0.0%) >0.99 Immune
Thrombocytopenic Purpura 0 (0.0%) 1 (0.0%) >0.99 Catheter Site
Hemorrhage 0 (0.0%) 1 (0.0%) >0.99 Mouth Hemorrhage 0 (0.0%) 1
(0.0%) >0.99 Esophageal Hemorrhage 0 (0.0%) 1 (0.0%) >0.99
Cerebral Hemorrhage 0 (0.0%) 2 (0.0%) 0.50 Pericardial Hemorrhage 0
(0.0%) 1 (0.0%) >0.99 Post Procedural Hematuria 0 (0.0%) 1
(0.0%) >0.99 Renal Hemorrhage 0 (0.0%) 1 (0.0%) >0.99
Retroperitoneal Hematoma 0 (0.0%) 1 (0.0%) >0.99 Traumatic
Intracranial Hemorrhage 0 (0.0%) 1 (0.0%) >0.99 Diverticulitis
Intestinal Hemorrhagic 0 (0.0%) 1 (0.0%) >0.99 Hemorrhagic
Duodenitis 0 (0.0%) 1 (0.0%) >0.99 Note: A treatment-emergent
adverse event (TEAE) is defined as an event that first occurs or
worsens in severity on or after the date of dispensing study drug
and within 30 days after the completion or withdrawal from study.
Percentages are based on the number of patients randomized to each
treatment group in the Safety population (N). Events that were
positively adjudicated as clinical endpoints are not included. All
adverse events are coded using the Medical Dictionary for
Regulatory Activities (MedDRA Version 20.1). .sup.[1]P value from
Fisher's Exact test. .sup.[2]Bleeding related events are identified
using the Hemorrhage terms (excl laboratory terms), a Standard
MedDRA Query (SMQ). .sup.[3]Gastrointestinal (GI) related bleeding
events are identified using the Gastrointestinal hemorrhage SMQ.
.sup.[4]Central nervous system (CNS) related bleeding events are
identified using the Central Nervous System hemorrhages and
cerebrovascular conditions SMQs. .sup.[5]Other bleeding events are
identified from the Hemorrhage terms (excl laboratory terms) SMQ
excluding GI bleeding and CNS bleeding.
Among the 8,179 patients (70.7% secondary prevention) followed for
a median 4.9 years, the primary endpoint occurred in 17.2% of
AMR101 patients versus 22.0% of placebo (HR, 0.75; 95% CI,
0.68-0.83; P<0.001) and the key secondary endpoint in 11.2%
versus 14.8% (HR, 0.74; 95% CI, 0.65-0.83; P<0.001). Additional
ischemic endpoints, assessed according to a prespecified
hierarchical schema, were significantly reduced, including
cardiovascular death (4.3% versus 5.2%; HR, 0.80; 95% CI,
0.66-0.98; P=0.03). Atrial fibrillation or flutter hospitalization
was more common with the AMR101 patients than the placebo patients
(3.1% versus 2.1%; P=0.004); serious bleeding occurred in 2.7% of
the AMR101 patients versus 2.1% in the placebo patients (P=0.06).
There were no significant differences between treatments in the
overall rate of treatment emergent adverse events or serious
adverse events leading to withdrawal of study drug as shown in
Table 20. The only serious adverse event occurring at a frequency
2% was pneumonia at 2.6% in the AMR101 group versus 2.9% in the
placebo group (P=0.42).
Conclusion
In this study, the risk of the primary composite endpoint of
cardiovascular death, nonfatal myocardial infarction, nonfatal
stroke, coronary revascularization, or unstable angina, assessed in
a time-to-event analysis, was significantly lower, by 25%, among
the patients who received 2 g of icosapent ethyl twice daily than
among those who received placebo, corresponding to an absolute
between-group difference of 4.8 percentage points in the rate of
the endpoint and a number needed to treat of 21. The risk of the
key secondary composite endpoint of cardiovascular death, nonfatal
myocardial infarction, or nonfatal stroke in a time-to-event
analysis was also significantly lower, by 26%, in patients who
received 2 g of icosapent ethyl twice daily than among those who
received placebo, corresponding to an absolute between-group
difference of 3.6 percentage points in the rate of the endpoint and
a number needed to treat of 28. Prespecified hierarchical testing
of other secondary endpoints revealed that the risks of a variety
of fatal and nonfatal ischemic events were lower in the AMR101
group than in the placebo group, including a 20% lower risk of
cardiovascular death. The benefits were observed against a
background of appropriate statin use among patients who had a
median LDL cholesterol level of 75.0 mg/dL at baseline.
Overall adverse event rates were similar across treatment groups.
There were numerically more serious adverse events related to
bleeding, though overall rates were low, with no fatal bleeding
observed in either group and no significant increase in adjudicated
hemorrhagic stroke or serious central nervous system or
gastrointestinal bleeding. There was a significantly higher rate of
hospitalization for atrial fibrillation or flutter, though rates
were low in those patients who received 2 g of icosapent ethyl
twice daily. Adverse event and serious adverse event rates leading
to study drug discontinuation were similar to placebo. The rates of
adverse events and serious adverse events leading to
discontinuation of trial drug were similar in the two groups.
The results from this study stand apart from the negative findings
of several recent trials of other agents that also lower
triglyceride levels, such as other omega-3 fatty acids,
extended-release niacin, fenofibrate, and cholesteryl ester
transfer protein-inhibitors. It is not known whether the lack of
benefit of omega-3 fatty acids in previous trials might be
attributable to the low dose or the low ratio of EPA to DHA. Both
the formulation (a highly purified and stable EPA acid ethyl ester)
and dose (4 grams daily) used in this study are different from all
prior omega-3 outcome trials. Despite utilizing a standard PROBE
design limitation of those previous trials included an open label
design without placebo, use of a low-intensity statin, and
conducted in a single country; in contrast to the present report,
patients in those trials had higher baseline LDL-C levels (182
mg/dL prior to statin initiation) and lower triglyceride values
(151 mg/dL). In contrast, the present study provides robust,
multinational data showing significant reductions in ischemic
events with administration of icosapent ethyl in patients with
well-controlled LDL-C. Metabolic data support that icosapent ethyl
does not raise LDL cholesterol levels, which DHA containing
formulations do.
A triglyceride level .gtoreq.150 mg/dL was required for inclusion
in this study however, owing to initial allowance for variability
in these levels and differences between qualifying and
randomization measurements, 10.3% of enrolled patients had
triglycerides less than 150 mg/dL on study entry. Cardiovascular
benefits appeared similar across baseline levels of triglycerides
(e.g., 135-149, 150 to 199, and 200 mg/dL or greater).
Additionally, the robust reduction in major adverse cardiovascular
events with administration of icosapent ethyl appeared to occur
irrespective of an achieved triglyceride level above or below 150
mg/dL at one year, suggesting that the cardiovascular risk
reduction was not tied to achieving a more normal (i.e., <150
mg/dL) triglyceride level. These observations suggest that at least
some of the impact of icosapent ethyl on the reduction in ischemic
events may be explained by metabolic effects other than
triglyceride lowering.
Mechanisms responsible for the benefit in the present study are
currently not known. The timing of divergence of the Kaplan-Meier
event curves suggests a delayed onset to benefit, which may reflect
the time to benefit from triglyceride reduction or other
mechanisms. The modestly higher rate of bleeding suggests that
there might be an anti-thrombotic mechanism of action. However, it
is unlikely that an anti-thrombotic effect would reduce elective
revascularization. Also, if the full explanation were an
antiplatelet or anticoagulant effect, one might expect a large
increase in major bleeding, which was not seen. Potentially,
membrane-stabilizing effects could explain part of the benefit.
Stabilization and/or regression of coronary plaque may also play a
part. The observation in the present study of a lower rate of
sudden cardiac death might support that mechanism, though this
finding should be viewed as exploratory. It is also possible that
the 40% reduction in hsCRP observed in patients from this trial may
contribute to benefit. Samples (e.g., serum and plasma) from
patients who participated in this trial have been banked for
biomarker and genetic analyses, which may provide more information
regarding mechanisms of action.
Regarding higher rates of diarrhea in the mineral oil placebo
group, a post hoc analysis excluding patients with diarrhea still
resulted in a significant risk reduction of 25% in the primary
endpoint. Also, there were no differences in the primary or key
secondary endpoints for placebo patients with an increase in LDL-C
compared to those with no change or a decrease in LDL-C.
In conclusion, AMR101 4 grams daily demonstrated similar overall
adverse event rates as placebo, and reduced important ischemic
events, including cardiovascular death, in statin-treated patients
with elevated triglycerides. Compared with placebo, icosapent ethyl
4 g per day significantly reduced cardiovascular events by 25%
including: a 31% reduction in heart attack, 28% reduction in
stroke, 31% reduction in myocardial infarction, and a 20% reduction
in death due to cardiovascular events.
The following are key conclusions obtained from this trial that
indicate a very favorable risk-benefit profile (1) significant
reduction in primary endpoint with a RRR of 24.8%, ARR of 4.8%, NNT
of 21, and a p-value of 0.00000001, (2) significant reduction in
key secondary endpoint with a RRR of 26.5%, ARR of 3.6%, NNT of 28,
and a p-value of 0.00000062, (3) consistent results across
subgroups to include triglycerides and secondary and primary
prevention, (4) consistent results across hierarchical secondary
endpoints to include cardiovascular death, (5) consistent results
across recurrent events, and (6) safety with a small but
insignificant increase in atrial fibrillation/flutter with low
event rates and non-significant increase in serious bleeding with
low event rates.
Example 2: The Impact of Icosapent Ethyl on Recurrent Events and
Total Ischemic Events in Statin-Treated Patients
Despite statin therapy, patients with established cardiovascular
disease or diabetes remain at high risk for, not only first but
also, recurrent ischemic events. The study results described in
Example 1 demonstrated that icosapent ethyl reduces the first
occurrence of the composite of cardiovascular death, nonfatal
myocardial infarction, nonfatal stroke, coronary revascularization,
or unstable angina, with a 25% relative risk reduction and a 4.8%
absolute risk reduction. The time to first occurrence of the
composite of cardiovascular death, nonfatal myocardial infarction,
and nonfatal stroke was also reduced with icosapent ethyl, with a
26% relative risk reduction and a 3.6% absolute risk reduction.
The objective of the following study was to assess the impact of
icosapent ethyl on recurrent events and total ischemic events. With
a greater number of events, it was contemplated that there might be
sufficient statistical power to examine the effect of icosapent
ethyl in the two separate cardiovascular risk strata in the trial:
patients with established atherosclerosis or patients with diabetes
plus at least one other cardiovascular risk factor. Accordingly,
the goal of the following study was to determine if icosapent ethyl
administered at 4 g per day (e.g., 2 g twice daily) reduces total
major adverse cardiovascular events in patients with fasting
triglycerides 150 and <500 mg/dL and LDL-cholesterol >40 and
.ltoreq.100 mg/dL who are at increased cardiovascular risk despite
statin therapy.
Study Design
The following study was a multi-center, placebo-controlled clinical
trial the details of which are described above in Example 1, the
REDUCE-IT design. As shown in FIG. 12, patients were randomized in
a double-blind manner to icosapent ethyl 4 g/day (2 grams twice
daily with food) versus placebo. Randomization was stratified by
cardiovascular risk cohort (i.e., secondary or primary prevention),
use of ezetimibe, and by geographic region.
Study Population
The study participants included patients with a history of
atherosclerosis or diabetes who were on statins and had fasting
triglycerides .gtoreq.150 and <500 mg/dL and LDL-cholesterol
>40 and .ltoreq.100 mg/dL. Of the study participants, 71% of the
patients had a history of atherosclerosis and 29% had a history of
diabetes. In order to be eligible for the trial, patients had to be
.gtoreq.45 years of age with either established cardiovascular
disease (i.e., secondary prevention stratum) or .gtoreq.50 years
old with type 2 or type 1 diabetes mellitus requiring treatment
with medication and at least one additional risk factor (i.e.,
primary prevention stratum).
The secondary prevention stratum consisted of patients with
documented coronary artery disease (.gtoreq.50% stenosis in at
least two major epicardial coronary arteries with or without prior
revascularization; prior MI; hospitalization for non-ST-segment
elevation acute coronary syndrome with ST-segment deviation or
positive biomarkers); documented cerebrovascular disease (prior
ischemic stroke: symptomatic .gtoreq.50% carotid stenosis;
asymptomatic carotid disease with .gtoreq.70% stenosis; history of
carotid revascularization); or documented peripheral artery disease
(ankle-brachial index <0.9 with symptoms of intermittent
claudication; history of aorto-iliac or peripheral surgery or
intervention).
The primary prevention stratum consisted of patients with no
documented cardiovascular disease as defined above, with diabetes,
and with at least one of the following cardiovascular risk factors:
men .gtoreq.55 years of age or women .gtoreq.65 years of age;
cigarette smoker or stopped smoking within 3 months before first
visit; blood pressure .gtoreq.140 mmHg systolic or .gtoreq.90 mmHg
diastolic or on antihypertensive medication; HDL-cholesterol
.ltoreq.40 mg/dL for men or .ltoreq.50 mg/dL for women; hsCRP >3
mg/L; creatinine clearance >30 and <60 mL/min;
non-proliferative retinopathy, pre-proliferative retinopathy,
proliferative retinopathy, maculopathy, advanced diabetic eye
disease or a history of photocoagulation; micro- or
macro-albuminuria; or asymptomatic ankle-brachial index
<0.9.
The participants were required to have fasting triglycerides
between 150 mg/dL and <500 mg/dL and LDL-cholesterol >40
mg/dL and 100 mg/dL. In the initial version of the clinical trial
protocol, a 10% allowance in qualifying triglyceride levels was
allowed, and therefore patients with triglycerides 135 mg/dL were
randomized. The study included 841 (10.3%) patients with baseline
triglyceride levels <150 mg/dL. After approximately 60% of the
patients were enrolled, an amendment changed the lower limit of
allowed triglyceride levels to 200 mg/dL with no variability
allowance. Patients were required to be on stable statin therapy
for at least four weeks.
Exclusion criteria for the study participants included severe heart
failure or liver disease, hemoglobin A1c levels >10.0%, planned
coronary intervention, familial lipoprotein lipase deficiency,
intolerance or hypersensitivity to statins, history of acute or
chronic pancreatitis, and hypersensitivity to fish, shellfish, or
ingredients of icosapent ethyl or placebo.
Main Outcomes and Measures
The primary outcome for the study was total recurrent events
consisting of the composite of cardiovascular death, nonfatal
myocardial infarction, nonfatal stroke, coronary revascularization,
or hospitalization for unstable angina. Recurrent event analyses
were also performed for the key secondary endpoint, a composite of
cardiovascular death, non-fatal myocardial infarction, or non-fatal
stroke. For each of these composite endpoints, the effects of
icosapent ethyl in the secondary and primary prevention strata were
examined separately.
Statistical Considerations
Demographic and baseline disease characteristics are presented
using frequencies and percentages for categorical variables and
medians with interquartile ranges for continuous variables. Between
treatment group comparisons were derived using the chi-square test
for categorical variables and Wilcoxon rank test for continuous
variables. All clinical endpoint events used in the efficacy
analyses were adjudicated by an independent Clinical Endpoint
Committee (CEC) who were blinded to the treatment assignment. Since
the primary efficacy endpoint was the time from randomization to
the first occurrence of any component of the composite endpoint,
and recurrence of such events within each patient is possible, a
pre-specified analysis using a Cox proportional-hazard with the
counting-process formulation of Andersen and Gill was performed to
model the first and all recurrent cardiovascular events. Hazard
ratios (HR) and corresponding 95% confidence intervals (CI) are
reported from this model. In addition, as a marginal model and an
extension of survival models based on the Cox proportional hazard
model, the modified Wei-Lin-Weissfeld (WLW) method for analysis of
recurrent events in the presence of deaths was carried out as a
supportive analysis. In addition, as pre-specified, a recurrent
event analysis using the Andersen-Gill and Wei-Lin-Weissfeld
methods were carried out for the individual primary event
components other than CV death. Though not pre-specified,
additional recurrent event analyses were performed for the key
secondary endpoint, which is a composite of CV death, non-fatal MI,
or non-fatal stroke, and for the primary endpoint and the key
secondary endpoint in the primary and secondary prevention strata
to explore further the consistency of clinical benefit of icosapent
ethyl. In subgroup analyses of the two cardiovascular risk strata
(i.e., primary and secondary prevention), site-level discrepancies
in cardiovascular risk group assignment occurring at entry and
detected during the study (1.8%) were adjusted to conform with
documented medical history data prior to randomization. All
efficacy analyses were performed according to the
intention-to-treat principle. All tests were based on a 2-sided
nominal significance level of 5% with no adjustments for multiple
comparisons.
Results
Baseline Characteristics
A total of 8,179 patients were randomized and followed for a median
of 4.9 years. The patients were well matched in the icosapent ethyl
and placebo groups as shown in Table 16 (See Example 1). The
secondary and primary prevention according to the adjusted
stratification for this study are shown in Table 26.
TABLE-US-00027 TABLE 26 Secondary and Primary Prevent Per Adjusted
Stratification for Patients Randomized to Placebo or Icosapent
Ethyl. Icosapent ethyl Placebo (N = 4089) (N = 4090)
p-value.sup.[1] Stratification Factors 0.7367 Secondary Prevention
per 2933 (71.7%) 2920 (71.4%) Adjusted Stratification Primary
Prevention per 1156 (28.3%) 1170 (28.6%) Adjusted Stratification
.sup.[1]P-value is from a Wilcoxon rank-sum test for continuous
variables and a chi-square test for categorical variables.
At baseline, the patient's median triglyceride levels were 216
mg/dL and median LDL-C levels were 75 mg/dL. Additional baseline
characteristics of the patients with no events, a single event, and
multiple recurrent events are shown in Table 27.
TABLE-US-00028 TABLE 27 Baseline Characteristics of Patients with
No Events, a Single Event, or Multiple Events. Baseline
Characteristics in Patients with No Events, a Single Event, or
Multiple Events No Events 1 Event Multiple Events (N = 6573) (N =
844) (N = 762) p-value.sup.[1] Demographics Age (years), Median
63.0 (57.0-69.0) 65.0 (59.0-71.0) 64.0 (58.0-70.0) <.0001
(Q1-Q3) Age .gtoreq.65 years, n (%) 2939 (44.7%) 456 (54.0%) 368
(48.3%) <.0001 Male, n (%) 4556 (69.3%) 661 (78.3%) 605 (79.4%)
<.0001 White, n (%).sup.[2] 5921 (90.1%) 765 (90.6%) 693 (90.9%)
0.6908 BMI (kg/m.sup.2), Median 30.8 (27.8-34.6) 31.1 (27.8-34.7)
30.8 (28.0-34.2) 0.5124 (Q1-Q3) BMI .gtoreq.30, n (%).sup.[3] 3762
(57.2%) 499 (59.1%) 432 (56.7%) 0.7771 Stratification Factors
Geographic Region, <.0001 n (%) Westernized.sup.[4] 4547 (69.2%)
639 (75.7%) 625 (82.0%) Eastern Europe.sup.[5] 1796 (27.3%) 185
(21.9%) 125 (16.4%) Asia Pacific.sup.[6] 230 (3.5%) 20 (2.4%) 12
(1.6%) CV Risk Category as <.0001 Randomized, n (%) Secondary
Prevention 4488 (68.3%) 640 (75.8%) 657 (86.2%) per Randomization
Primary Prevention per 2085 (31.7%) 204 (24.2%) 105 (13.8%)
Randomization CV Risk Category <.0001 Actual, n (%) Secondary
Prevention 4537 (69.0%) 652 (77.3%) 664 (87.1%) per Adjusted
Stratification Primary Prevention per 2036 (31.0%) 192 (22.7%) 98
(12.9%) Adjusted Stratification Ezetimibe Use, n (%) 401 (6.1%) 59
(7.0%) 64 (8.4%) 0.0378 Statin Intensity and Diabetes Status Statin
Intensity, n (%) 0.0819 Low 428 (6.5%) 49 (5.8%) 44 (5.8%) Moderate
4141 (63.0%) 519 (61.5%) 448 (58.8%) High 1974 (30.0%) 274 (32.5%)
268 (35.2%) Missing 30 (0.5%) 2 (0.2%) 2 (0.3%) Diabetes, n (%)
0.5535 Type I Diabetes 44 (0.7%) 5 (0.6%) 8 (1.0%) Type II Diabetes
3773 (57.4%) 511 (60.5%) 445 (58.4%) Both Type I and Type 1 (0.0%)
0 0 II Diabetes No Diabetes at 2752 (41.9%) 328 (38.9%) 309 (40.6%)
Baseline Missing 3 (0.0%) 0 0 Laboratory Measurements hsCRP (mg/L),
Median 2.1 (1.1-4.4) 2.4 (1.2-5.3) 2.4 (1.2-4.6) 0.0004 (Q1-Q3)
Triglycerides (mg/dL), 215.5 (176.0-272.0) 215.5 (175.0-270.3)
223.0 (178.5-285.5) 0.05- 39 Median (Q1-Q3) HDL-C (mg/dL), Median
40.0 (35.0-46.0) 39.5 (34.4-45.5) 38.8 (33.5-44.5) <.0001
(Q1-Q3) LDL-C (mg/dL), Median 75.0 (62.0-89.0) 75.0 (63.0-88.0)
75.0 (63.0-89.0) 0.9903 (Q1-Q3) Triglycerides Category 0.3523
<150 mg/dL 686 (10.4%) 79 (9.4%) 76 (10.0%) 150 to <200 mg/dL
1922 (29.2%) 259 (30.7%) 203 (26.6%) .gtoreq.200 mg/dL 3961 (60.3%)
506 (60.0%) 483 (63.4%) Triglycerides .gtoreq.200 mg/dL 1254
(19.1%) 173 (20.5%) 190 (24.9%) 0.0005 and HDL-C .ltoreq.35 mg/dL
EPA (.mu.g/mL), Median 26.2 (17.2-40.3) 24.6 (15.9-36.7) 26.9
(17.7-40.2) 0.0141 (Q1-Q3) In general, the baseline value is
defined as the last non-missing measurement obtained prior to the
randomization. The baseline LDL-C value obtained via preparative
ultracentrifugation was used, unless this value was missing. If the
LDL-C preparative ultracentrifugation value was missing, then
another LDL-C value was be used, with prioritization of values
obtained from LDL-C Direct measurements, followed by LDL-C derived
by the Friedewald calculation (only for subjects with TG <400
mg/dL), and finally LDL-C derived using the calculation published
by Johns Hopkins University investigators. For all other lipid and
lipoprotein marker parameters, wherever possible, baseline was
derived as the arithmetic mean of the Visit 2 (Day 0) value and the
preceding Visit 1 (or Visit 1.1) value. If only one of these values
was available, the single available value was used as baseline.
.sup.[1]P-value is from a Wilcoxon rank-sum test for continuous
variables and a chi-square test for categorical variables.
.sup.[2]Race as reported by the investigators. .sup.[3]Percentages
are based on the number of randomized subjects. .sup.[4]Westernized
region includes Australia, Canada, Netherlands, New Zealand, United
States, and South Africa. .sup.[5]Eastern European region includes
Poland, Romania, Russian Federation, and Ukraine. .sup.[6]Asia
Pacific region includes India.
Total Events for Primary Efficacy Endpoint: The total events for
the primary efficacy endpoint showed that of 8,179 patients, there
were 1,606 (i.e., 55.2% of the endpoints) first primary endpoints
and 1,303 (i.e., 44.8% of the endpoints) additional primary
endpoints, for a total of 2,909 endpoint events among the 1,606
patients. There were 762 second events, 272 third events, and 269
fourth or more events. FIG. 13 shows a distribution of first and
recurrent events in the patients randomized to icosapent ethyl or
placebo before and after the trial. In the overall trial, total
primary endpoints were reduced from 1,724 to 1,185 (HR 0.68, 95% CI
0.63-0.74, P<0.0001) with icosapent ethyl as shown in FIG. 13.
Within the primary endpoint reductions, first events were reduced
from 901 to 705 (i.e., a total reduction of 196), second events
were reduced from 463 to 299 (i.e., a total reduction of 164), and
additional endpoints were reduced from 360 to 131 (i.e., a total
reduction of 179) with icosapent ethyl (See FIG. 13). Using the
Wei-Lin-Weissfeld model, the first occurrence of a primary
composite endpoint was reduced with icosapent ethyl versus placebo
(HR 0.75, 95% CI 0.68-0.83, P<0.0001) as was the second
occurrence (HR 0.72, 95% CI 0.62-0.83, P<0.0001). FIGS. 14-16
depict the overall cumulative event curves from the primary
endpoint of cardiovascular death, nonfatal myocardial infarction,
nonfatal stroke, coronary revascularization, and unstable angina.
The overall cumulative events are shown in FIG. 14, the secondary
prevention stratum events are shown in FIG. 15, and the primary
prevention stratum events are shown in FIG. 16.
The total events for each occurrence of the primary endpoint,
inclusive of the first and all subsequent occurrences of primary
endpoints components (i.e., cardiovascular death, nonfatal
myocardial in fraction, nonfatal stroke, coronary
revascularization, and unstable angina) are shown in FIG. 17.
Importantly, FIG. 17 shows that the times to first occurrence,
second occurrence, third occurrence or fourth occurrence of the
primary composite endpoint were consistently reduced in the
icosapent ethyl group as compared to the placebo control group. The
proportions of first and subsequent primary endpoint events,
overall and by component, are depicted in FIG. 18. The risk
differences for every 100 patients treated for five years with
icosapent ethyl vs placebo control for the components of the
composite primary endpoint are shown in FIG. 19.
The total events for each component of the primary and key
secondary efficacy endpoints inclusive of the first and all
subsequent occurrences of the primary and key secondary endpoints
components (i.e., cardiovascular death, nonfatal myocardial in
fraction, nonfatal stroke, coronary revascularization, and unstable
angina) and key secondary endpoint components (i.e., nonfatal
myocardial infarction, nonfatal stroke, and cardiovascular death)
are shown in FIG. 20. Importantly, FIG. 20 shows that total events
for each component of the primary endpoint were also significantly
reduced. In the secondary prevention stratum, total primary
endpoint events were reduced from 1,468 to 988 (HR 0.66, 95% CI
0.61-0.72, P<0.0001), and in the primary prevention stratum,
from 256 to 197 (HR 0.79, 95% CI 0.65-0.96, P=0.018;
P.sub.interaction=0.098). Without adjusting for stratification
differences, total primary endpoint events in the secondary
prevention stratum were reduced from 1,461 to 964 (HR 0.65, 95% CI
0.60-0.71, P<0.0001) and from 263 to 221 (HR 0.86, 95% CI
0.71-1.03, P=0.105) in the primary prevention stratum;
P.sub.interaction=0.009.
Total Events for the Key Secondary Efficacy Endpoint: FIGS. 21-23
depict the cumulative event curves from the key secondary endpoint
of cardiovascular death, nonfatal myocardial infarction, and
nonfatal stroke. The overall cumulative events are shown in FIG.
21, the secondary prevention stratum events are shown in FIG. 22,
and the primary prevention stratum events are shown in FIG. 23.
Total key secondary endpoints were significantly reduced from 861
to 590 (HR 0.71, 95% CI 0.63-0.79, P<0.0001) with icosapent
ethyl versus placebo as shown in FIG. 21. Similar patterns were
seen for the key secondary endpoint, both in the secondary
prevention (HR 0.70, 95% CI 0.63-0.79, P<0.0001) and primary
prevention (HR 0.71, 95% CI 0.55-0.93, P=0.011) strata as shown in
FIGS. 22 and 23, respectively, P.sub.interaction=0.90. Without
adjustment for stratification differences, total key secondary
endpoint events in the secondary prevention stratum were reduced
from 671 to 478 (HR 0.69, 95% CI 0.61-0.78, P<0.0001) and from
142 to 112 (HR 0.78, 95% CI 0.60-1.00, P=0.047) in primary
prevention; P.sub.interaction=0.39.
Similarly, the total events for the primary and key secondary
efficacy endpoints are further depicted in FIGS. 24-29 as a
function of the total cumulative incidence vs years since
randomization. This contrasts FIGS. 14-16 and FIGS. 21-23 which
report the total events for the primary and key secondary efficacy
endpoints as a function of the mean cumulative function vs follow
up time in days from randomization. FIGS. 24 and 25 show the
overall mean cumulative recurrent events of the primary composite
endpoint and key secondary endpoint, respectively. FIGS. 26 and 27
depict the recurrent events of primary and key secondary endpoints
for the secondary prevention stratum, respectively. Lastly, FIGS.
28 and 29 further depict the recurrent events of primary and key
secondary endpoints for the primary prevention stratum,
respectively.
Overall, the results of this study indicated that the use icosapent
ethyl was superior as compared to a placebo in reducing total
ischemic events, with a consistent benefit in secondary as well as
primary prevention.
Conclusion
This study, an analysis of the total events in the REDUCE-IT trial
as outlined above in Example 1, indicated a significant reduction
in ischemic events with icosapent ethyl versus placebo. More
specifically, the results from this study show that there was a 32%
relative risk reduction and in total events for the primary
composite efficacy outcome. In addition, first events were reduced
by 25%, second events were reduced by 28%, and third or more events
were reduced by 50%. For every 100 patients treated with icosapent
ethyl for five years, approximately 16 total primary endpoint
events could be prevented: 1 cardiovascular death, 4 myocardial
infarctions, 1 stroke, 8 coronary revascularizations, and 2
episodes of unstable angina. An examination of total events for the
key secondary endpoint corroborated the significant reduction in
important ischemic events seen with the primary endpoint. There was
a consistent benefit in both the secondary prevention and primary
prevention strata.
There were significant reductions in the number of total events for
each individual component of the composite primary endpoint. This
benefit of icosapent ethyl across a variety of different endpoints
(i.e., coronary, cerebral, fatal, non-fatal, ischemic events,
revascularizations) suggests that the drug benefit is not likely to
be explained by triglyceride lowering alone but rather, strongly
suggests that there are multiple mechanisms of action of the drug
beyond triglyceride lowering that work together to achieve the
observed benefits. Basic investigations support this contention.
Icosapent ethyl was well tolerated with no significant difference
in rates of serious adverse events versus placebo. Although overall
rates were low in both treatment groups, and none of the events
were fatal, there was a trend towards increased serious bleeding
with no significant increases in adjudicated hemorrhagic stroke,
serious central nervous system bleeding, or gastrointestinal
bleeding. There was a small, but statistically significant increase
in hospitalization for atrial fibrillation or flutter noted in the
REDUCE-IT study as described in Example 1. Nevertheless, the large
number of important ischemic events averted, including a
significant reduction in cardiovascular death, provides a very
favorable risk-benefit profile. Given the broad inclusion criteria
and relatively few exclusion criteria, these results are likely
generalizable to a large proportion of statin-treated patients with
atherosclerosis or diabetes.
In conclusion, icosapent ethyl 4 g per day (i.e., 2 g per day)
significantly reduces total ischemic events in patients with
established atherosclerosis or with diabetes and additional
cardiovascular risk factors already being treated with statin
therapy, with consistent benefits across a variety of individual
ischemic endpoints. In patients with elevated triglycerides with
cardiovascular disease or diabetes, icosapent ethyl reduces total
ischemic events in both secondary and primary prevention. In such
patients with fasting triglycerides 135 mg/dL and above, icosapent
ethyl should be considered in order to reduce the total burden of
atherosclerotic events.
Example 3: The Impact of Icosapent Ethyl on Total Ischemic Events
in Statin-Treated Patients
As described above in Example 1, in time-to-first-event analyses,
icosapent ethyl significantly reduced the risk of ischemic events,
including cardiovascular death, among patients with elevated
triglycerides receiving statins. However, these patients remain at
risk for first and subsequent ischemic events. Results from Example
2 indicated that the use icosapent ethyl was superior as compared
to a placebo in reducing total ischemic events, with a consistent
benefit in secondary as well as primary prevention. The objective
of the study described in this example was to use pre-specified
analyses to determine the extent to which icosapent ethyl reduced
total ischemic events in patients from the REDUCE-IT trial.
Methods
The following study was a multi-center, placebo-controlled clinical
trial the details of which are described above in Example 1, the
REDUCE-IT design. Briefly, the REDUCE-IT trial randomized 8,179
statin-treated patients with triglycerides 135 and <500 mg/dL
(median baseline of 216 mg/dL) and LDL-cholesterol >40 and 100
mg/dL (median baseline of 75 mg/dL), and a history of
atherosclerosis (i.e., 71% patients) or diabetes (i.e., 29%
patients) to icosapent ethyl 4 g per day or placebo. The main
outcomes were total primary composite endpoint events defined as
cardiovascular death, nonfatal myocardial infarction, nonfatal
stroke, coronary revascularization, or hospitalization for unstable
angina and total key secondary composite endpoint events defined as
cardiovascular death, nonfatal myocardial infarction, or nonfatal
stroke. In the context of this study, total events refer to any
first event as well as any subsequent event. Differences in total
events were determined using other statistical models, including
Andersen-Gill, Wei-Lin-Weisfeld (Li and Lagakos), both
pre-specified, and a post hoc and joint-frailty analysis.
For the present prespecified analysis, the primary outcome was the
total of first plus subsequent ischemic events consisting of the
composite of cardiovascular death, nonfatal myocardial infarction,
nonfatal stroke, coronary revascularization, or hospitalization for
unstable angina. The composite of hard major adverse cardiovascular
events (i.e., cardiovascular death, non-fatal myocardial
infarction, non-fatal stroke) are designated as the "key secondary
endpoint" per suggestions from the Food and Drug Administration.
Exploratory analyses of the total of first and subsequent events
were also performed for the key secondary composite endpoint.
Baseline characteristics were compared between treatment groups
using the chi-squared test for categorical variables and the
Wilcoxon rank sum test for continuous variables. There are several
methods for analyzing first and subsequent (recurrent) event data.
As a pre-specified statistical method, a negative binomial
regression was used to calculate rates and rate ratios for total
cardiovascular events, which accounts for the variability in each
patient's risk of events. As pre-specified supportive analyses, the
modified Wei-Lin-Weissfeld method (Li and Lagakos modification) was
used to calculate hazard ratios (HRs) for the time to the first
event, second event, or third event. An additional pre-specified
analysis, the Andersen-Gill model using a Cox proportional-hazard
with the counting-process formulation was performed to model the
total events. In addition, in order to account for informative
censoring due to cardiovascular death, the HR for total non-fatal
events was calculated using a joint frailty model (See Rondeau V.
Joint frailty models for recurring events and death using maximum
penalized likelihood estimation: application on cancer events.
Biostatistics. 2007; 8:708-21). The joint frailty model
simultaneously estimates hazard functions for non-fatal and fatal
CV events and takes into account the fact that patients who are
prone to have nonfatal events have an elevated risk of a
cardiovascular death. The application of the joint frailty model
used a gamma distribution for the frailty term.
To improve the performance and validity of the statistical models,
a bundling approach was employed, whereby non-fatal events
occurring on the same day as a CV death were excluded, and at most,
one non-fatal event was counted on any given day (e.g., for
coronary revascularization occurring after a myocardial infarction
which eventually resulted in the patient's death, only the death
would be included). Statistical analyses using the full adjudicated
endpoint events dataset without exclusions using this bundling
approach were also determined.
All efficacy analyses were conducted in accordance with the
intention-to-treat principle. All tests were based on a 2-sided
nominal significance level of 5% with no adjustments for multiple
comparisons, consistent with prespecified plans for such
endpoints.
Results
A total of 8,179 patients were randomized and followed for a median
of 4.9 years. The baseline characteristics were well matched across
the icosapent ethyl and placebo groups as shown in Table 28. At
baseline, the median triglyceride levels were 216 mg/dL with median
LDL-C levels of 75 mg/dL. Additional baseline characteristics
across treatment groups and for patients with no events, a single
event, and multiple subsequent events are shown in Tables 28 and
29, respectively.
TABLE-US-00029 TABLE 28 Baseline Characteristics of Patients in
Icosapent Ethyl and Placebo Treatment Groups Icosapent Ethyl
Placebo (N = 4089) (N = 4090) P Value.sup.[1] Demographics Age
(years), Median (Q1-Q3) 64.0 (57.0-69.0) 64.0 (57.0-69.0) 0.7446
Age .gtoreq.65 years, n (%) 1857 (45.4%) 1906 (46.6%) 0.2815 Male,
n (%) 2927 (71.6%) 2895 (70.8%) 0.4245 White, n (%).sup.[2] 3691
(90.3%) 3688 (90.2%) 0.9110 BMI (kg/m.sup.2), Median (Q1-Q3) 30.8
(27.8-34.5) 30.8 (27.9-34.7) 0.3247 BMI .gtoreq.30, n (%).sup.[3]
2331 (57.0%) 2362 (57.8%) 0.5287 Stratification Factors Geographic
Region, n (%) 0.9924 Westernized.sup.[4] 2906 (71.1%) 2905 (71.0%)
Eastern Europe.sup.[5] 1053 (25.8%) 1053 (25.7%) Asia
Pacific.sup.[6] 130 (3.2%) 132 (3.2%) CV Risk Category, n (%)
0.9943 Secondary Prevention 2892 (70.7%) 2893 (70.7%) Primary
Prevention 1197 (29.3%) 1197 (29.3%) Ezetimibe Use, n (%) 262
(6.4%) 262 (6.4%) 0.9977 Statin Intensity and Diabetes Status
Statin Intensity, n (%) 0.1551 Low 254 (6.2%) 267 (6.5%) Moderate
2533 (61.9%) 2575 (63.0%) High 1290 (31.5%) 1226 (30.0%) Missing 12
(0.3%) 22 (0.5%) Diabetes, n (%) 0.9926 Type I Diabetes 27 (0.7%)
30 (0.7%) Type II Diabetes 2367 (57.9%) 2363 (57.8%) No Diabetes at
Baseline 1695 (41.5%) 1694 (41.4%) Missing 0 3 (0.1%) Laboratory
Measurements hsCRP (mg/L), Median (Q1-Q3) 2.2 (1.1-4.5) 2.1
(1.1-4.5) 0.7197 Triglycerides (mg/dL), Median (Q1-Q3) 216.5
(176.5-272.0) 216.0 (175.5-274.0) 0.9120 HDL-C (mg/dL), Median
(Q1-Q3) 40.0 (34.5-46.0) 40.0 (35.0-46.0) 0.1370 LDL-C (mg/dL),
Median (Q1-Q3) 74.5 (62.0-88.0) 76.0 (63.0-89.0) 0.0284 LDL-C
Tertiles, n(%) 0.0556 Lowest (.ltoreq.67 mg/dL) 14831 (36.2%) 1386
(33.9%) Middle (>67-.ltoreq.84 mg/dL) 1347 (32.9%) 1364 (33.3%)
Upper (>84 mg/dL) 1258 (30.8%) 1339 (32.7%) Missing 3 (0.1%) 1
Triglycerides Category, n (%) 0.8297 <150 mg/dL 412 (10.1%) 429
(10.5%) 150 to <200 mg/dL 1193 (29.2%) 1191 (29.1%) .gtoreq.200
mg/dL 2481 (60.7%) 2469 (60.4%) Triglyceride Tertiles, n (%) 0.4887
Lowest (.ltoreq.190 mg/dL) 1378 (33.7%) 1381 (33.8%) Middle
(>190-.ltoreq.250 mg/dL) 1370 (33.5%) 1326 (32.4%) Upper
(>250 mg/dL) 1338 (32.7%) 1382 (33.8%) Missing 3 (0.1%) 1
Triglycerides .gtoreq.200 mg/dL and HDL-C .ltoreq.35 mg/dL, n 823
(20.1%) 794 (19.4%) 0.4019 (%) EPA (.mu.g/mL), Median (Q1-Q3) 26.1
(17.1-40.1) 26.1 (17.1-39.9) 0.8867 Cardiovascular Disease
History.sup.[7] Prior Atherosclerotic Cardiovascular Disease 2816
(68.9%) 2835 (69.3%) 0.6667 (ASCVD), n (%) Prior Atherosclerotic
Coronary Artery Disease and 2387 (58.4%) 2393 (58.5%) 0.9107
Related Morbidities Ischemic Dilated Cardiomyopathy 137 (3.4%) 109
(2.7%) 0.0702 Myocardial Infarction 1938 (47.4%) 1881 (46.0%)
0.2065 Unstable Angina 1017 (24.9%) 1015 (24.8%) 0.9592 Prior
Atherosclerotic Cerebrovascular Disease and 641 (15.7%) 662 (16.2%)
0.5457 Related Morbidities, n (%) Carotid Disease 343 (8.4%) 372
(9.1%) 0.2730 Ischemic Stroke 267 (6.5%) 242 (5.9%) 0.2529
Transient Ischemic Attack 194 (4.7%) 181 (4.4%) 0.4925 Prior
Atherosclerotic Peripheral Arterial Disease, n 387 (9.5%) 388
(9.5%) 1.0000 (%) ABI <0.9 Without Symptoms of Intermittent 97
(2.4%) 76 (1.9%) 0.1073 Claudication Peripheral Artery Disease 377
(9.2%) 377 (9.2%) 1.0000 Prior Non-Atherosclerotic Cardiovascular
Disease, n 3649 (89.2%) 3645 (89.1%) 0.8868 (%) Prior Structural
Cardiac Disorders 827 (20.2%) 866 (21.2%) 0.2997 Congestive Heart
Failure 703 (17.2%) 743 (18.2%) 0.2583 Hypertrophic Cardiomyopathy
23 (0.6%) 20 (0.5%) 0.6507 Non-Ischemic Dilated Cardiomyopathy 35
(0.9%) 29 (0.7%) 0.4552 Non-Rheumatic Valvular Heart Disease 150
(3.7%) 163 (4.0%) 0.4892 Rheumatic Valvular Heart Disease 17 (0.4%)
9 (0.2%) 0.1215 Prior Cardiac Arrhythmias 229 (5.6%) 243 (5.9%)
0.5377 Atrio-Ventricular Block Above First Degree 51 (1.2%) 54
(1.3%) 0.8444 Sick Sinus Syndrome 30 (0.7%) 32 (0.8%) 0.8987
Supra-Ventricular Tachycardia Other Than Atrial 74 (1.8%) 77 (1.9%)
0.8696 Fibrillation/Atrial flutter Sustained Ventricular
Tachycardia 34 (0.8%) 34 (0.8%) 1.0000 Torsades De Pointes 1 (0.0%)
3 (0.1%) 0.6249 Ventricular Fibrillation 61 (1.5%) 65 (1.6%) 0.7877
Prior Non-Cardiac/Non-Atherosclerotic Vascular 3568 (87.3%) 3566
(87.2%) 0.9472 Disorders, n (%) Arterial Embolism 12 (0.3%) 9
(0.2%) 0.5229 Deep Vein Thrombosis 70 (1.7%) 60 (1.5%) 0.3785
Hypertension 3541 (86.6%) 3543 (86.6%) 0.9741 Hypotension 45 (1.1%)
33 (0.8%) 0.1745 Pulmonary Embolism 31 (0.8%) 42 (1.0%) 0.2396
Non-Ischemic Stroke 79 (1.9%) 84 (2.1%) 0.7518 Hemorrhagic Stroke
18 (0.4%) 22 (0.5%) 0.6350 Stroke of Unknown Origin 63 (1.5%) 62
(1.5%) 0.9285 Other Prior Conditions Metabolic Syndrome 507 (12.4%)
540 (13.2%) 0.2896 Baseline Laboratory Abnormalities, n (%) 1783
(43.6%) 1707 (41.7%) 0.0893 Renal Disorders 470 (11.5%) 429 (10.5%)
0.1474 Creatinine Clearance (CRCL) >30 and <60 ML/Min 309
(7.6%) 286 (7.0%) 0.3279 Macroalbuminuria 34 (0.8%) 24 (0.6%)
0.1909 Microalbuminuria 146 (3.6%) 134 (3.3%) 0.4664 Proteinuria 75
(1.8%) 63 (1.5%) 0.3046 Other Morbidities 173 (4.2%) 173 (4.2%)
1.0000 Pancreatitis 14 (0.3%) 9 (0.2%) 0.3067 Retinopathy 161
(3.9%) 167 (4.1%) 0.7782 Carotid Stenosis.sup.[8] n 316 346 Mean
(%) (SD) 59.0 (21.04) 56.9 (22.99) 0.4101 Medication Taken at
Baseline Anti-Diabetic, n (%) 2190 (53.6%) 2196 (53.7%) 0.9036
Anti-Hypertensive 3895 (95.3%) 3895 (95.2%) 0.9605
Anti-Platelet.sup.[9] 3257 (79.7%) 3236 (79.1%) 0.5514 One
Anti-platelet 2416 (59.09%) 2408 (58.88%) 0.8469 Two or more
Anti-platelets 841 (20.57%) 828 (20.4%) 0.7171 Anticoagulant 385
(9.4%) 390 (9.5%) 0.8531 Anticoagulant plus Anti-platelet 137
(3.4%) 137 (3.4%) 0.9984 No Antithrombotic 584 (14.3%) 601 (14.7%)
0.5965 ACE 2112 (51.7%) 2131 (52.1%) 0.6825 ARB 1108 (27.1%) 1096
(26.8%) 0.7598 ACE or ARB 3164 (77.4%) 3176 (77.7%) 0.7662 Beta
Blockers 2902 (71.0%) 2880 (70.4%) 0.5812 Abbreviations: ABI =
ankle brachial index, ACE = angiotensin-converting enzyme; ARB =
angiotensin receptor blockers. Percentages are based on the number
of subjects randomized to each treatment group in the ITT
population (N). In general, the baseline value is defined as the
last non-missing measurement obtained prior to the randomization.
The baseline LDL-C value obtained via Preparative
Ultracentrifugation was used, unless this value was missing. If the
LDL-C Preparative Ultracentrifugation value was missing, then
another LDL-C value was be used, with prioritization of values
obtained from LDL-C Direct measurements, followed by LDL-C derived
by the Friedewald calculation (only for subjects with TG <400
mg/dL), and finally LDL-C derived using the calculation published
by Johns Hopkins University investigators..sup.1For all other lipid
and lipoprotein marker parameters, wherever possible, baseline was
derived as the arithmetic mean of the Visit 2 (Day 0) value and the
preceding Visit 1 (or Visit 1.1) value. If only one of these values
was available, the single available value was used as baseline.
.sup.[1]P Values from Wilcoxon rank-sum test for continuous
variables and chi-square test for categorical variables.
.sup.[2]Race as reported by the investigators. .sup.[3]Body-mass
index is the weight in kilograms divided by the square of the
height in meters. .sup.[4]Westernized region includes Australia,
Canada, Netherlands, New Zealand, United States, and South Africa.
.sup.[5]Eastern European region includes Poland, Romania, Russian
Federation, and Ukraine. .sup.[6]Asia Pacific region includes
India. .sup.[7]The summary is based on the data collected from CV
history Case Report Form (CRF). .sup.[8]Two outliers of Carotid
Stenosis (%) with a value over 100% are excluded from the analysis.
Carotid Stenosis (%) data reported in categorical format of >x %
and <y % is analysed as x % and y %, respectively; and data
reported as x % to y % is analysed as an average of x % and y %.
.sup.[9]Dual anti-platelets were classified as such if both
components have a robust history of regulatory approval affirming
anti-platelet effects, thus excluding combinations where one
element lacks robust regulatory approval (e.g, Aspirin + Magnesium
Oxide is classified as a single agent because the latter component
lacks robust regulatory support as an anti-platelet agent).
TABLE-US-00030 TABLE 29 Baseline Characteristics of Patients with
No Primary Endpoint Events, a Single Event, or Multiple Events No
Events 1 Event Multiple Events P (N = 6573) (N = 844) (N = 762)
Value.sup.[1] Demographics Age (years), Median (Q1-Q3) 63.0
(57.0-69.0) 65.0 (59.0-71.0) 64.0 (58.0-70.0) 0.0400 Age .gtoreq.65
years, n (%) 2939 (44.7%) 456 (54.0%) 368 (48.3%) 0.0217 Male, n
(%) 4556 (69.3%) 661 (78.3%) 605 (79.4%) 0.5972 White, n
(%).sup.[2] 5921 (90.1%) 765 (90.6%) 693 (90.9%) 0.8328 BMI
(kg/m.sup.2), Median (Q1-Q3) 30.8 (27.8-34.6) 31.1 (27.8-34.7) 30.8
(28.0-34.2) 0.2609 BMI .gtoreq.30, n (%).sup.[3] 3762 (57.2%) 499
(59.1%) 432 (56.7%) 0.4656 Stratification Factors Geographic Region
0.0082 Westernized.sup.[4] 4547 (69.2%) 639 (75.7%) 625 (82.0%)
Eastern Europe.sup.[5] 1796 (27.3%) 185 (21.9%) 125 (16.4%) Asia
Pacific.sup.[6] 230 (3.5%) 20 (2.4%) 12 (1.6%) CV Risk Category as
<.0001 Randomized, n (%) Secondary Prevention 4488 (68.3%) 640
(75.8%) 657 (86.2%) Primary Prevention 2085 (31.7%) 204 (24.2%) 105
(13.8%) Ezetimibe Use, n (%) 401 (6.1%) 59 (7.0%) 64 (8.4%) 0.2892
Statin Intensity and Diabetes Status Statin Intensity, n (%) 0.7138
Low 436 (6.6%) 52 (6.2%) 44 (5.8%) Moderate 4153 (63.2%) 520
(61.6%) 451 (59.2%) High 1953 (29.7%) 270 (32.0%) 265 (34.8%)
Missing 31 (0.5%) 2 (0.2%) 2 (0.3%) Diabetes, n (%) 0.4420 Type I
44 (0.7%) 5 (0.6%) 8 (1.0%) Type II 3773 (57.4%) 511 (60.5%) 445
(58.4%) No Diabetes at Baseline 2752 (41.9%) 328 (38.9%) 309
(40.6%) Missing 3 (0.0%) 0 0 Laboratory Measurements hsCRP (mg/L),
Median (Q1-Q3) 2.1 (1.1-4.4) 2.4 (1.2-5.3) 2.4 (1.2-4.6) 0.3325
Triglycerides (mg/dL), Median 215.5 (176.0-272.0) 215.5
(175.0-270.3) 223.0 (178.5-285.5) 0.0701- (Q1-Q3) HDL-C (mg/dL),
Median (Q1-Q3) 40.0 (35.0-46.0) 39.5 (34.4-45.5) 38.8 (33.5-44.5)
0.0631 LDL-C (mg/dL), Median (Q1-Q3) 75.0 (62.0-89.0) 75.0
(63.0-88.0) 75.0 (63.0-89.0) 0.7384 LDL-C Tertiles, n (%) 0.5416
Lowest (.ltoreq.67 mg/dL) 2321 (35.3%) 283 (33.5%) 263 (34.5%)
Middle (>67-.ltoreq.84 mg/dL) 2156 (32.8%) 302 (35.8%) 253
(33.2%) Upper (>84 mg/dL) 2092 (31.8%) 259 (30.7%) 246 (32.3%)
Triglyceride Category <150 mg/dL 686 (10.4%) 79 (9.4%) 76
(10.0%) 150 to .ltoreq.200 mg/dL 1922 (29.2%) 259 (30.7%) 203
(26.6%) .gtoreq.200 mg/dL 3961 (60.3%) 506 (60.0%) 483 (63.4%)
Triglyceride Tertiles, n (%) 0.1993 Lowest (.ltoreq.190 mg/dL) 2235
(34.0%) 287 (34.0%) 237 (31.1%) Middle (>190-.ltoreq.250 mg/dL)
2167 (33.0%) 283 (33.5%) 246 (32.3%) Upper (>250 mg/dL) 2167
(33.0%) 274 (32.5%) 279 (36.6%) Lowest Triglycerides .gtoreq.200
mg/dL and 1254 (19.1%) 173 (20.5%) 190 (24.9%) 0.0336 HDL-C
.ltoreq.35 mg/dL EPA (.mu.g/mL), Median (Q1-Q3) 26.2 (17.2-40.4)
24.6 (15.9-36.7) 26.9 (17.7-40.2) 0.0120 Cardiovascular Disease
History.sup.[7] Prior Atherosclerotic 4370 (66.5%) 633 (75.0%) 648
(85.0%) <.0001 Cardiovascular Disease Prior Atherosclerotic
Coronary 3662 (55.7%) 542 (64.2%) 576 (75.6%) <.0001 Artery
Disease and Related Morbidities Myocardial Infarction 2931 (44.6%)
430 (50.9%) 458 (60.1%) <.0002 Unstable Angina 1497 (22.8%) 236
(28.0%) 299 (39.2%) <.0001 Ischemic Dilated 164 (2.5%) 46 (5.5%)
36 (4.7%) 0.5707 Cardiomyopathy Prior Atherosclerotic 965 (14.7%)
173 (20.5%) 165 (21.7%) 0.5816 Cerebrovascular Disease and Carotid
Disease 543 (8.3%) 90 (10.7%) 82 (10.8%) 1.0000 Ischemic Stroke 380
(5.8%) 64 (7.6%) 65 (8.5%) 0.5203 Transient Ischemic Attack 254
(3.9%) 61 (7.2%) 60 (7.9%) 0.6371 Prior Atherosclerotic 548 (8.3%)
109 (12.9%) 118 (15.5%) 0.115 Peripheral Arterial Disease
Peripheral Artery Disease 534 (8.1%) 106 (12.6%) 114 (15.0%) 0.1679
ABI <0.9 Without Symptoms 132 (2.0%) 24 (2.8%) 17 (2.2%) 0.5269
of Intermittent Claudication Prior Non-Atherosclerotic 5836 (88.8%)
775 (91.8%) 683 (89.6%) 0.1420 Cardiovascular Disease Prior
Structural Cardiac 1289 (19.6%) 234 (27.7%) 170 (22.3%) 0.0133
Disorders Congestive Heart Failure 1099 (16.7%) 200 (23.7%) 147
(19.3%) 0.0337 Hypertrophic 32 (0.5%) 6 (0.7%) 5 (0.7%) 1.0000
Cardiomyopathy Non-Ischemic Dilated 49 (0.7%) 11 (1.3%) 4 (0.5%)
0.1239 Cardiomyopathy Non-Rheumatic Valvular 225 (3.4%) 54 (6.4%)
34 (4.5%) 0.0996 Heart Disease Rheumatic Valvular Heart 22 (0.3%) 3
(0.4%) 1 (0.1%) 0.6265 Disease Prior Cardiac Arrhythmias 354 (5.4%)
65 (7.7%) 53 (7.0%) 0.6323 Atrio-Ventricular Block 77 (1.2%) 15
(1.8%) 13 (1.7%) 1.0000 Above First Degree Sick Sinus Syndrome 49
(0.7%) 5 (0.6%) 8 (1.0%) 0.4056 Supra-Ventricular 115 (1.7%) 24
(2.8%) 12 (1.6%) 0.0934 Tachycardia Other Than Atrial
fibrillation/Atrial flutter Sustained Ventricular 50 (0.8%) 10
(1.2%) 8 (1.0%) 0.8179 Tachycardia Torsades De Pointes 3 (0.0%) 0
(0.0%) 1 (0.1%) 0.4744 Ventricular Fibrillation 95 (1.4%) 16 (1.9%)
15 (2.0%) 1.0000 Prior Non-Cardiac/Non- 5716 (87.0%) 752 (89.1%)
666 (87.4%) 0.3125 Atherosclerotic Vascular Disorders Hypotension
52 (0.8%) 9 (1.1%) 17 (2.2%) 0.0754 Hypertension 5669 (86.2%) 750
(88.9%) 665 (87.3%) 0.3544 Non-Ischemic Stroke 123 (1.9%) 24 (2.8%)
16 (2.1%) 0.4231 Hemorrhagic Stroke 32 (0.5%) 4 (0.5%) 4 (0.5%)
1.0000 Stroke of Unknown Origin 92 (1.4%) 20 (2.4%) 13 (1.7%)
0.3826 Arterial Embolism 9 (0.1%) 11 (1.3%) 1 (0.1%) 0.0069 Deep
Vein Thrombosis 90 (1.4%) 20 (2.4%) 20 (2.6%) 0.7514 Pulmonary
Embolism 49 (0.7%) 12 (1.4%) 12 (1.6%) 0.8391 Other Prior
Conditions or 4870 (74.1%) 642 (76.1%) 587 (77.0%) 0.6799
Investigations Influencing Cardiovascular Risk Prior Metabolic
Disorders 3988 (60.7%) 530 (62.8%) 477 (62.6%) 0.9588 Diabetes Type
I 45 (0.7%) 5 (0.6%) 8 (1.0%) 0.4056 Diabetes Type II 3774 (57.4%)
511 (60.5%) 445 (58.4%) 0.3872 Metabolic Syndrome 843 (12.8%) 108
(12.8%) 96 (12.6%) 0.9402 Baseline Laboratory 2725 (41.5%) 395
(46.8%) 370 (48.6%) 0.4842 Abnormalities Renal Disorders 660
(10.0%) 129 (15.3%) 110 (14.4%) 0.6737 Creatinine Clearance >30
430 (6.5%) 83 (9.8%) 82 (10.8%) 0.5651 And <60 mL/Min
Proteinuria 100 (1.5%) 20 (2.4%) 18 (2.4%) 1.0000 Macroalbuminuria
43 (0.7%) 7 (0.8%) 8 (1.0%) 0.7964 Microalbuminuria 217 (3.3%) 38
(4.5%) 25 (3.3%) 0.2468 Other Morbidities 275 (4.2%) 42 (5.0%) 29
(3.8%) 0.2754 Pancreatitis 19 (0.3%) 2 (0.2%) 2 (0.3%) 1.0000
Retinopathy 259 (3.9%) 42 (5.0%) 27 (3.5%) 0.1758 Carotid
Stenosis.sup.[8] n 503 86 73 Mean (%) (SD) 57.0 (21.94) 58.2
(22.85) 63.5 (21.67) 0.1582 Medication Taken at Baseline
Anti-Diabetic 3498 (53.2%) 478 (56.6%) 410 (53.8%) 0.2548
Anti-Hypertensive 6239 (94.9%) 817 (96.8%) 734 (96.3%) 0.6008
Anti-Platelet 5138 (78.2%) 691 (81.9%) 664 (87.1%) 0.0037 One
Anti-platelet 3912 (59.52%) 486 (57.58%) 426 (55.91%) 0.4980 Two or
more Anti-platelets 1226 (18.65%) 205 (24.29%) 238 (31.23%) 0.0019
Anticoagulant 560 (8.5%) 125 (14.8%) 90 (11.8%) 0.0780
Anticoagulant plus Anti-platelet 185 (2.8%) 46 (5.5%) 43 (5.6%)
0.8661 No Antithrombotic 1060 (16.1%) 74 (8.8%) 51 (6.7%) 0.1212
ACE 3424 (52.1%) 429 (50.8%) 390 (51.2%) 0.8880 ARB 1743 (26.5%)
235 (27.8%) 226 (29.7%) 0.4220 ACE or ARB 5090 (77.4%) 645 (76.4%)
605 (79.4%) 0.1518 Beta Blockers 4541 (69.1%) 655 (77.6%) 586
(76.9%) 0.7368 Abbreviations: ABI = ankle brachial index; ACE =
angiotensin-converting enzyme; ARB = angiotensin receptor blockers.
In general, the baseline value is defined as the last non-missing
measurement obtained prior to the randomization. The baseline LDL-C
value obtained via Preparative Ultracentrifugation was used, unless
this value was missing. If the LDL-C preparative
ultracentrifugation value was missing, then another LDL-C value was
used, with prioritization of values obtained from LDL-C Direct
measurements, followed by LDL-C derived by the Friedewald
calculation (only for subjects with TG <400 mg/dL), and finally
LDL-C derived using the calculation published by Johns Hopkins
University investigators. For all other lipid and lipoprotein
marker parameters, wherever possible, baseline was derived as the
arithmetic mean of the Visit 2 (Day 0) value and the preceding
Visit 1 (or Visit 1.1) value. If only one of these values was
available, the single available value was used as baseline.
.sup.[1]P-value comparing Single Event group with Multiple Events
group is from a Wilcoxon test for continuous variables and a
Fishers Exact test for categorical variables. .sup.[2]Race as
reported by the investigators. .sup.[3]Body-mass index is the
weight in kilograms divided by the square of the height in meters.
.sup.[4]Westernized region includes Australia, Canada, Netherlands,
New Zealand, United States, and South Africa. .sup.[5]Eastern
European region includes Poland, Romania, Russian Federation, and
Ukraine. .sup.[6]Asia Pacific region includes India. .sup.[7]The
summary is based on the data collected from CV history Case Report
Form (CRF). .sup.[8]Two outliers of Carotid Stenosis (%) with a
value over 100% are excluded from the analysis. Carotid Stenosis
(%) data reported in categorical format of >x % and <y % is
analysed as x % and y %, respectively; and data reported as x % to
y % is analysed as an average of x % and y %. .sup.[9]Dual
anti-platelets were classified as such if both components have a
robust history of regulatory approval affirming anti-platelet
effects, thus excluding combinations where one element lacks robust
regulatory approval (e.g. Aspirin + Magnesium Oxide is classified
as a single agent because the latter component lacks robust
regulatory support as an anti-platelet agent).
At baseline the percentage of patients taking at least one other
cardiovascular medication including antiplatelet agents was (79.7
and 79.1%), beta blockers (71.0% and 70.4%), angiotensin converting
enzyme (ACE) inhibitors (51.7% and 52.1%), or angiotensin receptor
blockers (27.1% and 26.8%) in the icosapent ethyl and placebo
treatment arms, respectively.
Total Events for the Primary Efficacy Endpoint: Across 8,179
randomized patients, there were 1,606 (i.e., 55.2%) first primary
endpoint events and 1,303 (i.e., 44.8%) additional primary endpoint
events, for a total of 2,909 endpoint events as shown in Table 30
and FIGS. 30, 31A and 31B.
TABLE-US-00031 TABLE 30 Total Primary and Key Secondary Composite
Endpoints Accounting for Statistical Handling of Multiple Endpoints
Occurring in a Single Calendar Day as a Single Event Primary
endpoint Key secondary endpoint Icosapent ethyl Placebo Overall
Icosapent ethyl Placebo Overall n (%) (N = 4089) (N = 4090) (N =
8179) (N = 4089) (N = 4090) (N = 8179) Total events before 1185
(40.7) 1724 (59.3) 2909* (100) 590 (42.0) 816 (58.0) 1406 (100)
reduction Total events after 1076 (41.0) 1546 (59.0) 2622 (100) 558
(42.1) 767 (57.9) 1325 (100) reduction.dagger. Fatal events 174
(45.0) 213 (55.0) 387 (100) 174 (45.0) 213 (55.0) 387 (100)
Non-fatal events 902 (40.4) 1333 (59.6) 2235 (100) 384 (40.9) 554
(59.1) 938 (100) Percentages are based on the total number of
randomized patients within each category. *A single event was
experienced by 844 patients (844 events) and 2 or more events were
experienced by 762 patients (2065) events, for a total of 1606
patients experiencing a total of 2909 events. .dagger.Reduction
means 1) any nonfatal events on the same day as death are removed
and 2) if 2 nonfatal events occur on the same day only the first
one is counted.
The proportions of first and subsequent primary endpoint events,
overall and by component type, are depicted in FIG. 32. There were
762 second events, 272 third events, and 269 fourth or more events.
Overall, total (i.e., first and subsequent) primary endpoint event
rates were reduced to 61 from 89 to per 1000 patient years (i.e.,
rate ratio (RR) 0.70, 95% CI 0.62-0.78, P<0.0001) with icosapent
ethyl as shown in the central illustration in FIG. 33. Using the
Wei-Lin-Weissfeld model, the first occurrence of a primary
composite endpoint was reduced with icosapent ethyl versus placebo
(i.e., HR 0.75, 95% CI 0.68-0.83, P<0.0001) as was the second
occurrence (i.e., HR 0.68, 95% CI 0.60-0.78, P <0.0001). There
was a 30% relative risk reduction in the total (first and
subsequent) ischemic events for the primary composite endpoint with
icosapent ethyl. First events were reduced by 25%, second events by
32%, third events by 31%, and fourth or more events by 48%.
The cumulative events over time are shown in FIGS. 34A and 34B.
Specifically, FIG. 34A depicts the total (i.e., first and
subsequent) and time to first primary composition endpoint events
and FIG. 34B shows the key secondary endpoint events. Total key
secondary endpoint event rates were significantly reduced to 32
from 44 per 1000 patient years for icosapent ethyl versus placebo,
respectively (i.e., RR 0.72, 95% CI 0.63-0.82, P<0.0001) with
icosapent ethyl versus placebo as shown in FIG. 34B. The times to
first occurrence, second occurrence, third occurrence or fourth
occurrence of the primary composite endpoint were consistently
reduced as shown FIG. 35 with icosapent ethyl. There were similar
results for the models irrespective of whether bundling and/or
single accounting was employed as shown in Tables-31-33.
TABLE-US-00032 TABLE 31 HRs for Pre-Specified Analyses of Total for
Primary and Key Secondary Composite Endpoint Events Using the
Reduced Dataset Primary composite endpoint Key secondary composite
endpoint Unadjusted Adjusted Unadjusted Adjusted RR/HR Unadjusted
RR/HR Adjusted RR/HR Unadjusted RR/HR Adjusted (95% CI) p-value
(95% CI) p-value (95% CI) p-value (95% CI) p-value Negative 0.68
1.5 .times. 10.sup.-10 0.70 3.6 .times. 10.sup.-10 0.71 8.9 .times.
10.sup.-7 0.72 7.1 .times. 10.sup.-7 binomial (0.61, 0.77) (0.62,
0.78) (0.62, 0.82) (0.63, 0.82) Andersen- 0.69 3.5 .times.
10.sup.-21 0.69 3.3 .times. 10.sup.-21 0.72 2.4 .times. 10.sup.-9
0.72 2.4 .times. 10.sup.-9 Gill (I) (0.64, 0.74) (0.64, 0.74)
(0.64, 0.80) (0.64, 0.80) Andersen- 0.69 9.1 .times. 10.sup.-11
0.69 5.2 .times. 10.sup.-11 0.72 1.2 .times. 10.sup.-6 0.72 1.0
.times. 10.sup.-6 Gill (II) (0.61, 0.77) (0.61, 0.77) (0.63, 0.82)
(0.63, 0.82) Modified First 0.76 2.7 .times. 10.sup.-8 0.75 1.6
.times. 10.sup.-8 0.74 7.4 .times. 10.sup.-7 0.74 7.0 .times.
10.sup.-7 WLW event (0.69, 0.83) (0.68, 0.83) (0.65, 0.83) (0.65,
0.83) Second 0.69 2.7 .times. 10.sup.-8 0.68 1.8 .times. 10.sup.-8
0.75 1.1 .times. 10.sup.-3 0.75 1.1 .times. 10.sup.-3 event (0.60,
0.79) (0.60, 0.78) (0.63, 0.89) (0.63, 0.89) Third 0.69 2.1 .times.
10.sup.-5 0.69 2.0 .times. 10.sup.-5 0.79 .0170 0.79 .0171 event
(0.59, 0.82) (0.59, 0.82) (0.65, 0.96) (0.65, 0.96) Rate ratios
(RR) are presented for results from negative binomial model; Hazard
ratios (HR) are presented for results from Andersen Gill (I) model,
Andersen Gill (II) model, and modified Wei-Lin-Weisfeld model.
Unadjusted analyses only included treatment group in the model;
Adjusted analyses also included stratification factors
(cardiovascular risk category, geographic region, and use of
ezetimibe) as covariate, in addition to treatment group in the
model. Andersen Gill (I) model is based on an intensity model with
model-based variance estimate and was a pre-specified methodology.
Andersen Gill (II) model is based on a proportional means model
with cluster-robust standard errors, with the cluster set to the
patient ID. This is a an updated methodology than the prespecified
method. Wei-Lin-Weisfeld model is based on Li-Lagarkos
modification. Analyses are based on reduced dataset accounting for
statistical handling of multiple endpoints occurring in a single
calendar day as a single event.
TABLE-US-00033 TABLE 32 Results from Joint Frailty Model for
Primary and Key Secondary Endpoints Using the Reduced Dataset
Non-fatal Cardiovascular Event Cardiovascular Death HR HR (95% CI)
P-value (95% CI) P-value Primary endpoint Unadjusted 0.66 7.40
.times. 10.sup.-17 0.80 0.0282 (0.60, 0.73) (0.65, 0.98) Adjusted
0.67 7.20 .times. 10.sup.-16 0.80 0.0306 (0.61, 0.74) (0.65, 0.98)
Key secondary Unadjusted 0.68 3.30 .times. 10.sup.-8 0.79 0.0366
endpoint (0.59, 0.78) (0.63, 0.99) Adjusted 0.68 4.30 .times.
10.sup.-8 0.79 0.0380 (0.59, 0.78) (0.63, 0.99) Joint frailty model
is based on Rondeau (See Rondeau V. Joint frailty models for
recurring events and death using maximum penalized likelihood
estimation: application on cancer events. Biostatistics. 2007; 8:
708-21) implemented in the frailty pack R package. Default settings
were used, except that 3 knots were used to model the baseline
hazard function (to improve speed given that we know from the mean
cumulative plots that the shape of the baseline hazard function is
unlikely to be complex) and recurrent AG == TRUE (i.e. thereby
assuming independence between events conditional on the frailty
term). Unadjusted analyses only included treatment group in the
model; Adjusted analyses also included stratification factors
(cardiovascular risk category, geographic region, and use of
ezetimibe) as covariate, in addition to treatment group in the
model. Analyses are based on reduced dataset accounting for
statistical handling of multiple endpoints occurring in a single
calendar day as a single event.
TABLE-US-00034 TABLE 33 Hazard and Rate Ratios for Pre-Specified
Analyses for Primary and Key Secondary Endpoints Using the Full
Dataset Primary Composite Endpoint Key Secondary Composite Endpoint
Unadjusted Adjusted Unadjusted Adjusted RR/HR RR/HR RR/HR HR (95%
CI) p-value (95% CI) p-value (95% CI) p-value (95% CI) p-value
Negative binomial 0.67 .sup. 1.6 .times. 10.sup.-10 0.69 .sup. 4.4
.times. 10.sup.-10 0.71 1.4e-06 0.71 1.2 .times. 10.sup.-06 (0.60,
0.76) (0.61, 0.77) (0.62, 0.81) (0.62, 0.82) Andersen-Gill (I) 0.68
3.4e-22 0.68 3.0e-22 0.71 .sup. 1.8 .times. 10.sup.-10 0.71 1.7
.times. 10.sup.-10 (0.63, 0.74) (0.63, 0.74) (0.64, 0.79) (0.63,
0.79) Andersen-Gill (II) 0.68 .sup. 4.5 .times. 10.sup.-11 0.68
.sup. 3.4 .times. 10.sup.-11 0.71 4.1 .times. 10.sup.-7 0.71 3.4
.times. 10.sup.-07 (0.61, 0.77) (0.61, 0.76) (0.62, 0.81) (0.62,
0.81) Modified WLW First event 0.76 2.7 .times. 10.sup.-8 0.75 1.7
.times. 10.sup.-8 0.74 7.4 .times. 10.sup.-7 0.74 7.1 .times.
10.sup.-07 (0.69, 0.83) (0.68, 0.83) (0.65, 0.83) (0.65, 0.83)
Second event 0.69 4.6 .times. 10.sup.-9 0.68 3.1 .times. 10.sup.-9
0.75 0.0011 0.75 0.0011 (0.61, 0.78) (0.60, 0.78) (0.63, 0.89)
(0.63, 0.89) Third event 0.70 2.2 .times. 10.sup.-5 0.70 2.1
.times. 10.sup.-5 0.79 0.0170 0.79 0.0171 (0.60, 0.83) (0.60, 0.83)
(0.65, 0.96) (0.65, 0.96) Rate ratios (RR) are presented for
results from negative binomial model; Hazard ratios (HR) are
presented for results from Andersen Gill (I) model, Andersen Gill
(II) model, and modified Wei-Lin-Weisfeld model. Unadjusted
analyses only included treatment group in the model; Adjusted
analyses also included stratification factors (cardiovascular risk
category, geographic region, and use of ezetimibe) as covariate, in
addition to treatment group in the model. Negative Binomial model.
(add references) Andersen Gill (I) model is based on an intensity
model with model-based variance estimate and was a pre-specified
methodology. Andersen Gill (II) model is based on a proportional
means model with cluster-robust standard errors, with the cluster
set to the patient ID. This is a more standard methodology than the
prespecified method.
Total events for each component of the primary endpoint were also
significantly reduced as shown in FIG. 36, FIG. 30, and Table
34.
FIGS. 37A and 37B show the total primary and key secondary
composite endpoints in selected subgroup analyses by the negative
binomial model. The risk differences for every 1000 patients
treated for five years with icosapent ethyl for the five components
of the composite primary endpoint are shown in FIG. 38;
approximately 159 total primary endpoint events could be prevented
within that time frame: 12 cardiovascular deaths, 42 myocardial
infarctions, 14 strokes, 76 coronary revascularizations, and 16
episodes of hospitalization for unstable angina. FIGS. 39 and 40
show the forest plot for total primary and key secondary composite
endpoint events and first second, and third occurrences for the
reduced dataset with unadjusted and adjusted values, respectively.
FIGS. 41 and 42 show the forest plots for the total primary
composite endpoint events and total key secondary composite
endpoint events and first, second, and third occurrences for the
reduced data with unadjusted values, respectively. FIGS. 43 and 44
show the total primary composite endpoint events and key secondary
composite endpoint events and first, second, and third occurrences
for the reduced data set with adjusted values, respectively. FIGS.
45 and 46 show the total primary and key secondary composite
endpoint events and first, second, and third occurrences for the
full data set for the unadjusted and adjusted values,
respectively.
The study drug adherence in patients with recurrent events was also
explored. At the time of a first primary endpoint event (fatal or
nonfatal), 81.3% (573/705) of icosapent ethyl and 81.8% (737/901)
of placebo patients with a first primary endpoint event were
receiving randomized study drug. At the time of subsequent primary
endpoint events (fatal or nonfatal), 79.7% (188/236) and 79.5%
(299/376) of patients with a second event, 68.1% (49/72) and 74.1%
(106/143) of patients with a third event, and 68.0% (17/25) and
71.6% (48/67) of patients with a fourth event were receiving
randomized study drug in the icosapent ethyl and placebo groups,
respectively. Therefore, the majority of the first, second, third,
and fourth events occurred while patients were on randomized study
treatment. Numerical differences in study drug adherence among
patients with recurrent events were not statistically significant
between treatment groups.
Conclusion
In these total event analyses of the REDUCE-IT clinical trial as
described in Example 1, large and significant reductions in total
ischemic events with icosapent ethyl versus placebo were found in
the total event analyses. Three prespecified and one post hoc
analyses with various statistical methodologies demonstrated
consistent effects on total ischemic events, with substantial
relative and absolute risk reductions. There was a 30% relative
risk reduction in the total (i.e., first and subsequent) ischemic
events for the primary composite endpoint with icosapent ethyl. For
every 1000 patients treated with icosapent ethyl for five years,
approximately 159 total primary endpoint events could be prevented.
Total events for the hard MACE key secondary endpoint also
demonstrated large and clinically meaningful reductions, which
further corroborated the significant reduction in important
ischemic events seen with the primary endpoint.
There were significant reductions in the first, subsequent and
total ischemic events for each individual component of the
composite primary endpoint. This benefit of icosapent ethyl across
a variety of different ischemic endpoints (e.g., coronary,
cerebral, fatal and non-fatal events, and revascularizations)
suggests that the drug benefit is not likely to be explained by
triglyceride lowering alone and suggests strongly that there are
multiple mechanisms of action of the drug beyond triglyceride
lowering that may work together to achieve the observed
benefits.
Icosapent ethyl was well tolerated with no significant differences
in rates of serious adverse events versus placebo. Although overall
rates were low in both treatment groups, and none of the events
were fatal, with icosapent ethyl there was a trend towards
increased serious bleeding albeit with no significant increases in
adjudicated hemorrhagic stroke, serious central nervous system
bleeding, or gastrointestinal bleeding. There was a small, but
statistically significant increase in hospitalization for atrial
fibrillation or flutter endpoints observed in patients from the
clinical trial. Nevertheless, the large number of important
ischemic events averted with the drug, including a significant
reduction in fatal and nonfatal stroke (28%), cardiac arrest (48%),
sudden death (31%) and cardiovascular death (20%), in indicative of
a very favorable risk-benefit profile.
The patients for the REDUCE-IT clinical trial represent a
population at high risk for ischemic events, as suggested by the
annualized placebo event rate (5.74%), which was expected per study
design and is consistent with historical data for similar high-risk
statin-treated patient populations. It is therefore not surprising
that the total atherosclerotic event burden was also high for
REDUCE-IT patients. Substantial and consistent risk reduction with
icosapent ethyl was observed in total event analyses for the
primary endpoint, each contributing component, and the key
secondary endpoint. Time-to-first-event results provide low number
needed to treat (NNT) values (i.e., 21 for the primary endpoint; 28
for the key secondary endpoint); the total event analyses results
provide incremental evidence of substantial reduction of the total
atherosclerotic burden with icosapent ethyl in these patients, with
16 total primary events prevented for every 100 patients treated
with icosapent ethyl for 5 years. Without intending to be bound by
any particular theory, given the broad inclusion criteria and
relatively few exclusion criteria, these results may be
generalizable to a large proportion of at-risk statin-treated
patients with atherosclerosis or diabetes.
Study drug adherence in patients with recurrent events was strong
in both treatment groups at the time of their first primary
endpoint event, decreasing somewhat across both treatment groups
from the occurrence of the first to the fourth event. For example,
at the time of a first occurrence of a fatal or nonfatal primary
endpoint event, 81.3% of icosapent ethyl and 81.8% of placebo
patients with a first primary endpoint event were on study drug;
these rates decreased to 68.0% and 71.6% for patients with a fourth
primary endpoint event.
The primary study results for the REDUCE-IT trial and the recurrent
and total endpoint event findings discussed herein stand in stark
contrast to cardiovascular outcome studies with other agents that
lower triglyceride levels and with low-dose omega-3 fatty acid
mixtures, where cardiovascular outcome benefit has not been
consistently observed in statin-treated patients. EPA has unique
lipid and lipoprotein, anti-inflammatory, anti-platelet,
anti-thrombotic, and cellular modifying effects, all of which may
contribute to benefits in atherosclerotic processes such as reduced
development, slowed progression, and increased stabilization of
atherosclerotic plaque. The aggregate contribution of these
EPA-related effects may contribute to the large observed reductions
in total ischemic events with icosapent ethyl.
Each total event analysis model employed in this study provides
statistical handling of subsequent events, with some distinct and
some overlapping strengths. Despite differences in statistical
methodologies, the consistency of findings across the models speaks
to the robustness of the study conclusions and the underlying
outcomes data.
In conclusion, icosapent ethyl four grams daily (i.e., administered
two grams twice daily) significantly reduces total ischemic events
in statin-treated patients with well-controlled LDL-C and
cardiovascular risk factors including elevated triglycerides with
consistent benefits observed across a variety of individual
ischemic endpoints. In such patients, icosapent ethyl presents an
important treatment option to further reduce the total burden of
atherosclerotic events beyond that provided by statin therapy
alone.
Example 4: The Impact of Icosapent Ethyl on Ischemic Events in
Statin-Treated Patients as a Function of Baseline Triglyceride
Tertile
The objective of the following example was to determine the extent
to which icosapent ethyl reduced ischemic events in patients from
the REDUCE-IT trial, as described in Example 1 as a function of
triglyceride level.
In the REDUCE-IT trial as described in Example 1, patients
underwent a screening visit to determine eligibility, including
testing of statin-stabilized triglyceride levels. If patients met
inclusion and exclusion criteria, including triglyceride levels,
they could then be entered into the study at a subsequent
randomization visit. Triglyceride levels were also measured from
blood drawn at the randomization visit, but randomization values
were not utilized for study qualification. Randomization values did
not always fall within the inclusion criteria that were previously
met within qualifying visits. In total, the baseline triglyceride
levels of the patients ranged from 81 mg/dL to 1401 mg/dL.
The patients were then categorized into three tertiles based on
their triglyceride levels. The lowest tertile range included those
patients with triglyceride levels of .gtoreq.81 to .ltoreq.190
mg/dL with a median triglyceride level of 163 mg/dL, the middle
tertile range included those patients with triglycerides of >190
to .ltoreq.250 mg/dL with a median triglyceride level of 217 mg/dL,
and the uppermost tertile range included patients with triglyceride
levels of >250 to .ltoreq.1401 mg/dL with a median triglyceride
level 304 mg/dL. The baseline characteristics of the patients to
include the triglyceride category by tertile are shown below in
Table 34.
TABLE-US-00035 TABLE 34 Baseline Characteristics of Patients
Icosapent Ethyl Placebo (N = 4089) (N = 4090) Age (Years) 64 64
Female, % 28.4% 29.2% CV Risk Category, % Secondary Prevention
Cohort 70.7% 70.7% Primary Prevention Cohort 29.3% 29.3% Prior
Atherosclerotic Cardiovascular Disease, % 68.9% 69.3% Prior
Atherosclerotic Cerebrovascular Disease, % 15.7% 662 (16.2%) Prior
Atherosclerotic Peripheral Artery Disease, % 9.5% 388 (9.5%) LDL-C
(mg/dL), Median (Q1-Q3) 74.0 (61.5-88.0) 76.0 (63.0-89.0)
Triglycerides (mg/dL), Median (Q1-Q3) 216.5 (176.5-272.0) 216.0
(175.5-274.0) Triglycerides Category (by Tertiles)* .gtoreq.81 to
.ltoreq.190 mg/dL Median 163 mg/dL >190 to .ltoreq.250 mg/dL
Median 217 mg/dL >250 to .ltoreq.1401 mg/dL Median 304 mg/dL
FIG. 47 is a forest plot demonstrating that the total events (i.e.,
first and subsequent) for the primary composite endpoint of CV
death, non-fatal stroke, non-fatal myocardial infarction, coronary
revascularizations, or unstable angina requiring hospitalization
was reduced in all patients across the entire triglyceride range
and within each of the defined triglyceride tertiles. Similarly,
FIG. 48 demonstrates that the time to first event of the primary
composition endpoint was reduced across the entire triglyceride
range.
In conclusion, patients from the REDUCE-IT clinical trial with
baseline triglyceride levels across all tertiles (e.g., between 81
mg/di to 1410 mg/dl), regardless of their specific triglyceride
baseline level, benefited from the administration of 4 g of
icosapent ethyl per day and experienced statistically significant
reductions in not only the time to first cardiovascular event, but
also, total cardiovascular events in both the primary and key
secondary composite endpoints.
The results from the REDUCE-IT clinical trial showed a significant
cardiovascular benefit associated with the administration of
icosapent ethyl. It is contemplated that a number of factors
contribute to the significant reduction in the cardiovascular risk.
Without intending to be bound by any particular theory, one of the
contributing factors might relate to the dose and formulation of
the icosapent ethyl administered to the patients, in marked
contrast to previous studies of omega-3 fatty acid studies. An
additional contributing factor could relate to the patients' blood
pressure. For example, prespecified exploratory analyses of
icosapent ethyl with no adjustment for multiple comparisons showed
average placebo-corrected reductions from baseline in systolic
blood pressure of 1.3 mm Hg (95% CI, 0.9 to 1.6) and in diastolic
blood pressure of 0.5 mm Hg (95% CI, 0.3 to 0.7) as shown in FIG.
49. FIG. 49 shows repeated-measurements analysis of change from
baseline blood pressure over time by a mixed effects model for the
ITT population (icosapent ethyl: n=4089, placebo: n=4091, maximum
number of observations per patient=6). These differences appear to
be modest, but it is contemplated, that they might contribute to
the benefits of icosapent ethyl. It is further contemplated that
biomarkers (e.g., the ratio of EPA to arachidonic acid) and blood
pressure, may also provide an understanding of the effects of
icosapent ethyl and potential mechanistic insight for the observed
reduction in cardiovascular risk. Further, as common in long-term
clinical trials, study drug adherence waned overtime. However,
despite the waning there was a long-sustained treatment effect on
total events as shown in FIG. 50.
* * * * *
References